Next Article in Journal
Lethal and Non-Lethal Functions of Caspases in the DNA Damage Response
Next Article in Special Issue
Early Dietary Exposures Epigenetically Program Mammary Cancer Susceptibility through Igf1-Mediated Expansion of the Mammary Stem Cell Compartment
Previous Article in Journal
Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease
Previous Article in Special Issue
Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

IGF2: Development, Genetic and Epigenetic Abnormalities

1
Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, F-75012 Paris, France
2
Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University, F-75012 Paris, France
*
Author to whom correspondence should be addressed.
Cells 2022, 11(12), 1886; https://doi.org/10.3390/cells11121886
Submission received: 1 May 2022 / Revised: 4 June 2022 / Accepted: 6 June 2022 / Published: 10 June 2022
(This article belongs to the Collection Insulin-Like Growth Factors in Development, Cancers and Aging)

Abstract

:
In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 (Igf2) knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving innovative techniques have shed light on the complex regulation of IGF2 expression. The physiological roles of IGF-II have also been documented, revealing pleiotropic tissue-specific and developmental-stage-dependent action. Furthermore, in recent years, animal studies have highlighted important interspecies differences in IGF-II function, gene expression and regulation. The identification of human disorders due to impaired IGF2 gene expression has also helped to elucidate the major role of IGF-II in growth and in tumor proliferation. The Silver–Russell and Beckwith–Wiedemann syndromes are the most representative imprinted disorders, as they constitute both phenotypic and molecular mirrors of IGF2-linked abnormalities. The characterization of patients with either epigenetic or genetic defects altering IGF2 expression has confirmed the central role of IGF-II in human growth regulation, particularly before birth, and its effects on broader body functions, such as metabolism or tumor susceptibility. Given the long-term health impact of these rare disorders, it is important to understand the consequences of IGF2 defects in these patients.

1. Introduction

Insulin-like growth factor two (IGF-II) is a key protein regulating growth, particularly during normal fetal development, but it is also often dysregulated during tumorigenesis [1,2,3]. In this review, we focus on the role of IGF-II in physiological functions and its regulation by cis or trans genetic factors. We do not consider here the role of IGF-II in the context of tumors, or its regulation by environmental factors.
IGF-II belongs to a larger system including several different regulatory factors and generally referred to as the “IGF system” that we will briefly present. IGF-I and IGF-II are the main ligands of the type 1 IGF receptor (IGF-1R). This tyrosine kinase receptor is composed of an extracellular domain consisting of an alpha chain, a transmembrane domain, and an intracellular domain consisting of a beta chain carrying the tyrosine kinase sites. The ligand binds dimerized IGF-1R and transmit the resulting signal (Figure 1) [4].
The binding of IGF-I or IGF-II to IGF-1R leads to activation of the downstream MAP kinase and PI3 kinase signaling pathways [5,6]. IGF-1R has a higher affinity for IGF-I than for IGF-II (Kd = 1.5 nM and 3.0 nM, respectively) [7,8]. Thanks to its high degree of similarity to IGF-1R, the insulin receptor (INSR) can also bind IGFs, but with negligible affinity for IGF-I, and with only type A INSR having a five-fold lower affinity for IGF-II than for insulin [9,10]. Another receptor, the type 2 IGF receptor (IGF-2R), which is a mannose-6-phosphate cation-dependent receptor, also specifically binds IGF-II [11,12,13]. Its role has been demonstrated in IGF-II clearance through lysosomal degradation and more recent studies in rodents stated for its role in memory enhancement processes [14,15,16,17,18]. The plasma half-lives of both IGF-I and IGF-II are extended by binding proteins (IGFBP). Six different IGFBPs have been identified, each with relative different affinities between IGFs but binding IGFs with a higher affinity than IGF-1R [19,20,21,22,23]. IGFBP-3 and -5 can also form a larger complex with the acid-labile subunit (ALS), which can bind IGFs, increasing the stability of these factors in the blood [24]. The bioavailability of IGFs is dependent from the homeostasis between their bound and free forms which is regulated through IGFBP proteolysis [23,25,26,27,28]. As an illustrating example, PAPP-A2 (Pregnancy-associated Plasma Protein-A2) is a metalloproteinase which specifically cleaves IGF from IGFBP-3 and -5 to allow IGF activity [29,30]. Recently, pathogenic variation in PAPPA2 has been reported in growth-retarded children resulting from decreased IGF bioactivity [31].
IGF-II is secreted, mostly via the placenta, during pregnancy [32,33]. After birth, the IGF-II circulating in the bloodstream for the greater part results from secretion from hepatocytes, but unlike that of IGF-I, this secretion is not dependent on growth hormone (GH) secretion [34,35].
IGF-II synthesis results from the expression of IGF2, an imprinted gene located in the chromosome 11p15.5 region. Imprinted genes are characterized by their monoallelic expression, which is dependent on the parental origin of the allele. This pattern of expression is controlled by epigenetic marks on differentially methylated regions (DMR) known as imprinting control regions (ICR) [36,37]. In the 11p15.5 region, H19/IGF2: InterGenic-DMR (IG-DMR or ICR1) is methylated on the paternal allele, driving the expression of the paternal IGF2 allele, whereas the absence of methylation on the maternal allele leads to the expression of H19, a non-coding transcript (Figure 2).

2. Structural and Regulation Aspects

2.1. Main Characteristics, Linear Organization

In 2019, Baral et al. unraveled the complexity of the genomic and transcriptional organization of the IGF2/Igf2 locus, by using human or mouse DNA segments as queries in genome analyses, and RNA sequencing libraries (complete review in [38]). IGF2 (ENSG00000167244) is composed of 10 exons and five promoters, whereas its mouse counterpart is located on chromosome 7, and is composed of eight exons and four promoters.
The five human IGF2 promoters control the expression of different non-coding exons, but all transcripts include exons 8–10, which encode the IGF-II protein precursor and the 3′ untranslated RNA. Human promoters 1 and 2 (P1 and P2) are species specific, and P2 regulates two classes of IGF2 transcripts differing due to alternative splicing of exon 5 (Figure 3).
The human-secreted IGF-II is composed of 67 amino acids organized into four domains, the B, C, A, and D domains (listed in order from the N- to the C-terminus) [39]. Two types of protein precursors with different presumptive N-terminal signal peptides (consisting of 24 or 80 amino acids) give rise to mature human IGF-II, depending on the inclusion or exclusion of exon 5 in the IGF2 mRNA. The E peptide of the IGF-II precursor (also named “big” IGF-II), encoded by the 3-’end mRNA, is 89 amino acids long (Figure 3). It has been involved in paraneoplastic pancreatic independent hypoglycemia [40,41].
The 11p15.5 locus also includes H19, which is separated from IGF2 by about 80 kb (Figure 2). In both humans and mice, IGF2 and H19 are imprinted in a reciprocal manner. Moore et al. detected three Igf2 antisense transcripts relative to P0 transcription, with no open reading frames, in mice [42]. The exact role of these transcripts is unclear, and it is unknown whether their co-expression with the sense transcript (which has yet to be demonstrated), within the same cell, would influence mRNA stability.
Different protein-binding sites are involved in regulating the expression of these two genes. The first evidence of differences in protein-binding sites and methylation status between the two alleles came from DNA hypersensitive site studies on the mouse Igf2/H19 locus [43]. These studies revealed clear differences in nuclease sensitivity between the parental chromosomes, with the presence of mutually exclusive hypersensitive sites (on the maternal chromosome) and DNA methylation sites (on the paternal chromosome).
The specific parent-of-origin pattern of expression of H19 and IGF2 at 11p15.5 is controlled by the allele-specific methylation status of H19/IGF2:IG-DMR. This locus is composed of seven CTCF-binding sites (CBS1-7) located in the A and B blocks of repeated domains (Figure 2). CTCF is a highly conserved zinc-finger DNA-binding protein with multiple roles in gene regulation [44]. The region orthologous to ICR1 in mouse contains only four CBS at the Igf2 locus. Several studies in humans have reported methylation at all CBS in H19/IGF2:IG-DMR on the paternal allele and established a correlation between the methylation of these CBS and IGF2 expression from the paternal allele [45]. Our team has also demonstrated homogeneous methylation levels for all CBS in humans [46]. In mice, CTCF binding to the unmethylated maternal ICR is essential for imprint maintenance in somatic cells, providing protection against aberrant de novo methylation at DMR throughout the locus. Furthermore, CTCF acts as an insulator, and CTCF binding creates a small loop of silent chromatin (CTCF binding to the maternal ICR regulates its interaction with matrix attachment region (MAR)3 and DMR1 at Igf2) (Figure 4), preventing enhancers from gaining access to the Igf2 promoter [47]. H19/IGF2:IG-DMR methylation on the paternal allele abolishes CTCF binding and ICR-mediated insulation, resulting in functional communication between promoters and enhancers, and an activation of Igf2 expression (see below).
In addition to CBS, the human IGF2/H19 domain contains four binding sites for the pluripotency factors OCT4 and SOX2 [48]. There is evidence to suggest that the function of CTCF is modulated by the binding of OCT4/SOX2 to neighboring areas of DNA [49]. These factors play a role in maintaining or establishing the unmethylated status of the maternal allele. This hypothesis is strongly supported by in vitro experiments and by studies in transgenic mouse models showing that the OCT4/SOX2 binding sites in the maternal H19/IGF2:IG-DMR are essential for the full protection of DNA methylation during the establishment or maintenance phases [50,51]. Indeed, in humans, mutations of these OCT4/SOX2 binding sites in the maternal allele lead to hypermethylation of the CBS, followed by an increase in IGF2 expression leading to Beckwith–Wiedemann syndrome [52]. Two other factors, ZFP57 and ZNF445, protect ICR from DNA demethylation after fertilization. ZNF445 seems to be sufficient on its own in humans, whereas ZFP57 and ZNF445 cooperate in rodents (Figure 2) [53,54]. The IGF2/H19 domain also contains several other DMR: three within the IGF2 gene (DMR0, DMR1 and DMR2) and an additional DMR located in the H19 promoter (H19DMR), all of which are secondary DMR (somatic DMR that acquire their parent-specific DNA methylation mark in somatic diploid cells) methylated on the paternal allele [55] (Figure 2).

2.2. Three-Dimensional Organization

The regulation of IGF2 expression must be considered in three dimensions, with CTCF playing a major role in this aspect. There is experimental evidence to suggest that CTCF confers allele-specific effects on transcription via long-range chromatin interactions. The generation of these data was made possible by the emergence of 3C technology [56]. These interactions are dependent on the parental origin of the chromatin.
Series of deletions at the H19/Igf2 locus have made it possible to demonstrate the presence of several enhancers, two of which are predominantly endodermal and located 10 kb from the start site of the H19 transcript. These two enhancers target the H19 and Igf2 promoters, allowing expression of the corresponding genes (see below and Figure 2 and Figure 4) [57]. For the maternal allele, for which Igf2 expression is silent, 3C data are generally consistent with a model in which the CTCF-bound ICR contacts both the upstream DMR1 and a downstream matrix attachment region (MAR). Genetic studies have confirmed that CTCF binding to the ICR is required for both the formation of ICR-DMR1-MAR contacts and the prevention of maternal-specific enhancer-Igf2 promoter interactions. By contrast, on the paternal allele, which displays active Igf2 expression, all DMR sequences are methylated, preventing CTCF binding, and most of this region appears to be accessible, allowing more fluid contact with the enhancers [47,58].
Recent efforts to elucidate chromatin organization at the Igf2/H19 mouse locus, based on a combination of studies of allelic CTCF binding with both high-resolution and single-cell 3D chromatin organization assays, defined topologically associated domains (TAD) [59]. These studies determined the dynamic structure of the imprinted Igf2-H19 domain, and showed that CTCF binding occurred at multiple sites in both alleles, exclusively in ICR1 for the maternal. Furthermore, combinations of allelic 4C-seq and DNA-FISH revealed that CTCF binding to the paternal chromosome alone was correlated with a first level of sub-TAD structure. Additional CTCF binding to the differentially methylated region on the maternal chromosome adds a further layer of sub-TAD organization. This allele-specific sub-TAD organization may, thus, provide an instructive or permissive context for the correct activation of imprinted genes during development.
In humans, a specific parent-of-origin pattern of expression through TAD generation according to CTCF binding has been described, leading to IGF2 expression or silencing [60]. As in mice, the most important proteins for TAD architecture are CTCF (which bind to the ICR) (Figure 4). Moreover, crosstalk between IGF2/H19 and the CDKN1C/KCNQ1OT1 domain (another imprinted domain located in the same chromosome region) has been detected on the basis of a higher order of chromatin folding, suggesting the involvement of a mechanism for coordinating the expression of genes with the same expression status: IGF2 and KCNQ1OT1 on the paternal allele and H19 and CDKN1C on the maternal allele [60].

2.3. Trans-Regulation Mechanisms

In addition to being regulated by H19/IGF2:IG-DMR methylation and the three-dimensional organization of chromatin, IGF2 can be directly regulated through the activation of its promoters by several transcription factors, including those of the oncogenic HMGA2-PLAG1 pathway [61]. PLAG1 (pleiomorphic adenoma gene 1) overexpression was first observed in pleiomorphic adenomas of the salivary glands, identifying PLAG1 as an oncogene [62]. PLAG1 is a nuclear factor with seven zinc-finger domains that can bind IGF2 promoter P3, upregulating its transcriptional activity [62]. This finding has been confirmed in various other tumors, including hepatoblastomas, lipoblastomas and leukemia (review in [63]). Interestingly, Plag1 inactivation in mouse models results in pre- and postnatal growth retardation, despite an absence of change in Igf2 expression in embryos and pups [64].
HMGA2 (high mobility group AT-hook 2), initially named HMGI-C, is a member of the high-mobility group of proteins. Its expression is usually barely detectable in normal adult cells, but increases in cells transformed with viral oncogenes and in malignant tissues [65]. Mouse models of Hmga2 inactivation have a pygmy phenotype, with pre- and postnatal growth restriction and craniofacial abnormalities (a shortened head) [66]. The expression levels of HMGA2 and PLAG1 are highly correlated in thyroid tumors, and HMGA2 overexpression in cellular models is associated with an increase in PLAG1 expression [67].
The role of this oncogenic pathway in the control of IGF2 expression was highlighted in 2017, with the identification of additional mutations of HMGA2 and the first mutations of PLAG1 in patients referred for Silver–Russell syndrome (in addition to original mutations of IGF2). One of these PLAG1 mutations led to a downregulation of IGF2 expression in fibroblasts through a specific change in P3 promoter activity. Finally, the overexpression of HMGA2 and PLAG1 or their silencing in transfection assays result in a gain in expression or the downregulation of IGF2 expression, respectively [61].
DIS3L2 (DIS3-like 3′-5′ exoribonuclease 2) encodes a protein involved in the processing of mRNA and small non-coding RNAs. Homozygous loss-of-function variants of DIS3L2 lead to a rare condition called Perlman syndrome. This syndrome is characterized by excessive fetal growth and an increase in the risk of Wilms’ tumor [68]. In a mouse model, Dis3l2 invalidation was associated with an overexpression of Igf2 in nephron progenitor cells that was not associated with a loss of imprinting, as Igf2 still displayed monoallelic expression. The mechanism of Igf2 overexpression in this model remains to be determined [69].
Network of imprinted genes: In recent years, several studies in humans or animal models have shown that abnormalities at a given imprinted locus can impact at the expression of genes not only at the locus concerned, but also at other imprinted or non-imprinted loci [70,71,72,73]. This finding raised the possibility of an imprinted gene network, within which, imprinted genes are co-regulated. This pattern of regulation may partly account for the clinical overlap between imprinting disorders due to (epi)genetic defects at different imprinted loci [74]. For example, a strong clinical overlap between Silver–Russell syndrome (SRS, OMIM #180860) and Temple syndrome (TS14, OMIM #616222) has been described, despite the existence of several syndrome-specific traits, including pre- and postnatal growth restriction, relative macrocephaly, feeding difficulties and a protruding forehead [75]. IGF2 downregulation is thought to be the molecular mechanism underlying the SRS phenotype, with about 40% of SRS patients presenting hypomethylation at the H19/IGF2:IG-DMR [76]. TS14 is mostly due to abnormalities of the imprinted 14q32.2 locus. This locus contains non-coding RNA sequences that are expressed from the maternal allele only (including the two long non-coding RNA, MEG3 and MEG8). In cases of maternal uniparental disomy of chromosome 14 or hypomethylation at the MEG3/DLK1:IG-DMR, MEG3 and MEG8 are expressed from both the paternal and maternal alleles, leading to an increase in the level of expression of these two genes. Abnormally low levels of IGF2 expression have been reported in the fibroblasts of TS14 patients, despite normal H19/IGF2:IG-DMR methylation. Furthermore, in control fibroblasts, the overexpression of MEG3 and MEG8 leads to a downregulation of IGF2. Conversely, the silencing of MEG3 and/or MEG8 in control fibroblasts leads to an upregulation of IGF2 expression. Thus, MEG3 and MEG8, which are expressed from the maternal 14q32.2 locus, regulates IGF2 expression at 11p15.5, providing support for the hypothesis of an imprinted gene network [77].

3. Physiological Roles

3.1. IGF-II: A Key Factor in Development

IGF-II is a growth factor with a structural and regulatory complexity associated with pleiotropic tissue-specific and developmental-stage-dependent action (Figure 5).
Paternally expressed imprinted genes are usually associated with a pro-proliferative role during development. This is particularly true for the IGF2 gene, which encodes a key factor for feto-placental growth [78]. Indeed, IGF-II is highly mitogenic, and together with IGF-I, it promotes the proliferation of various types of cells during the fetal period, thereby playing a major role in organ growth and development.
In mice, the Igf2 gene plays a crucial role during the embryonic period. The P0 promoter operates specifically in the placenta, leading to extremely high levels of Igf2 expression in placental tissues during gestation. The complete inactivation of Igf2 (Igf2 null+mat/−pat), and specific inactivation of the placental transcript Igf2-P0 (Igf2 P0+mat/-pat) have been studied experimentally in mice. Igf2-null mice display intrauterine growth restriction and placental hypoplasia. Furthermore, the specific inactivation of Igf2-P0 leads to intrauterine growth restriction through placental restriction [36,79]. These mouse models also present changes to feto-maternal exchanges, including, in particular, the supply of maternal nutrients to the fetus [1,80]. These alterations can be explained by the role of the Igf2/Igf2R axis in placental vascularization and the adaptation of the placenta to fetal needs [81].
However, there are important differences between humans and mice, particularly in the placenta. For example, the human placenta is monochorial, with interanvil spaces, whereas the mouse placenta is trichorial and has a labyrinth region. Moreover, the human placenta is associated with some extremely specific molecular patterns, such as the expression of certain genes (miR-194, C19orf33, SIGLEC6, estrogens, glycodelin A, chorionic gonadotropins, etc.) [82,83]. Furthermore, in humans, IGF2-P0 is not specific to the placenta and is expressed in other tissues, including skeletal muscle. There is no clear evidence to suggest that the mouse model is strictly comparable to humans, so it remains unclear whether the same placental dysfunctions occur in mice and humans [55,84]. Data obtained from human placenta explants and the human BeWo cell (a choriocarcinoma cell line) model suggest that abnormalities in the functioning of the IGF system, including IGF2R impairment, in particular, would lead to an imbalance between proliferation and apoptosis in trophoblasts [85]. In addition, patients with SRS (i.e., with low levels of IGF2 expression, see below) display hypoplasia of the placenta and chorionic villi. Moreover, this hypoplasia is commonly associated with oligohydramnios, consistent with placental dysfunction in this syndrome [84]. By contrast, a study on patients with Beckwith–Wiedemann syndrome (BWS, #130650, see below) with various molecular etiologies showed that most individuals with BWS, which is caused by IGF2 overexpression, displayed placentomegaly [86,87]. These studies clearly show that deregulations of the IGF2 and IGF system can cause changes to placental structure and function in humans [85]. IGF2 is also highly expressed in fetal tissues, under the control of various promoters, depending on the tissue concerned, and is involved in the maturation and development of mesoderm-derived tissues, in particular [88,89,90,91].
In mice, Igf2 expression decreases rapidly in all tissues after birth, potentially accounting for the intrauterine growth phenotype but minimal effects on postnatal growth in Igf2-null mice [36,92]. However, Igf2 expression is maintained in the brain, particularly in the hippocampus, where it plays a role in memory processes, learning and brain plasticity [18,93,94]. This postnatal expression of Igf2 is also involved in homeostasis of stem cells niches in brain and intestine [95].
In humans, serum IGF-II concentration remains high (400–1000 ng/mL) during the postnatal period, despite the significant decrease in IGF2 expression observed in tissues. The exact physiological role of this circulating IGF-II and the absence of interference with the GH-IGF-I regulation, despite the fact that IGF-I and IGF-II have fairly similar affinities for IGF1R remains to be elucidated.
The IGF-II in serum is produced by the liver under the control of the P1 promoter and released into the bloodstream. The difference in postnatal IGF2 expression between humans and mice is thought to be due to the presence of the IGF2 P1 promoter in humans, and its absence in mice [96]. During the postnatal period, the P3 and P4 promoters are responsible for IGF2 expression in most tissues [34,89,96]. Interestingly, the P1 promoter is not imprinted (IGF2-P1 expression is, therefore, biallelic) and has been reported to be liver-specific, although doubts have been raised about this specificity following the demonstration that cells in other tissues, such as chondrocytes, express the IGF2-P1 transcript [34,96,97,98]. IGF2 displays monoallelic expression in the fetal liver, and is dependent mainly on the P3 and P4 imprinted promoters.

3.2. Some Roles of IGF-II in Tissues

The other roles of IGF-II in tissues, apart from those cell proliferation and organ growth, remain unclear. Many studies have sought to elucidate the role of IGF-II in the development, maintenance and function of various tissues. Loss- or gain-of-function models (mice or cellular models) have been developed to shed light on the mechanism of action of IGF-II.
Several studies in mice have shown that Igf-II is involved in endochondral ossification within the growth plate, which governs bone growth. Autocrine Igf-II in the growth plate activates the PI3K/Akt and TGF-β signaling pathways, leading to the expression of proliferative factors that stimulate chondrocyte proliferation, pro-osteogenic factors, such as BMP-9 and alkaline phosphatase, which mediate ossification, and constituents of cartilage, such as proteoglycans. Igf-II has also been implicated in partial regulation of the development and organization of the growth plate, through the regulation of glucose metabolism [99,100,101].
Other studies have revealed the role of IGF-II in angiogenesis. Igf-II promotes the mesodermal, and then endothelial differentiation of mouse embryonic stem cells. In HUVEC cells, IGF-II activates sprouting, leading to the activation of endothelial cells and vasodilation. IGF-II and IGF-1R are essential for the maintenance of tip cells, a particular type of endothelial cell responsible for guiding de novo angiogenesis. The binding of IGF-II to IGF1-R activates the PI3K/Akt signaling pathway, switching on the cell migration programs necessary for angiogenesis. IGF-binding proteins, such as IGFBP-3 and IGFBP-4, modulate the bioavailability of IGF-II, which regulates the effect of IGF-II on sprouting angiogenesis. IGF-II is also involved in angiogenesis through its role in maintaining hypoxia-induced factor α (HIF-α) levels, leading to expression of the vascular endothelial growth factor (VEGF) gene [102,103,104].
In human adipose tissue, IGF-II induces the differentiation of subcutaneous preadipocytes and inhibits the differentiation of visceral preadipocytes. IGF-II also downregulates the insulin receptor IR-A and expression of the glucose transporter GLUT4 in visceral adipocytes, thereby preventing the development of adiposity in visceral compartments [105].
In mouse fetal liver, Igf-II regulates glycogen production. Igf-II binds type A INSR, which activates the PI3K/Akt pathway, leading to the phosphorylation of glycogen synthase, which catalyzes the production of glycogen in fetal liver [106]. Igf-II is also involved in hepatocyte proliferation in mice [107].
Some studies on mouse models have postulated a role for Igf-II in the regulation of pancreatic size and function. Indeed, Igf-II synthesized in the pancreatic mesenchyme exerts a paracrine effect on the proliferation of pancreatic β-cells and, thus, on the size and function of the exocrine pancreas during the pre- and postnatal periods. By contrast, the autocrine Igf-II produced by pancreatic β-cells plays a role in adaptation to energy demands in pregnant mice [108,109,110].
One of the best-known and most-studied roles of IGF-II is that in myogenesis. IGF-II plays a direct role in the differentiation of mesoderm into myoblasts by upregulating the expression of MyoD, a key factor determining musculoskeletal fate. It also acts on striated skeletal muscle homeostasis and, thus, on the maturation, maintenance and healing of such muscles. In skeletal muscle, IGF2 transcription depends on the P3 promoter and the mTOR protein. IGF-II acts by binding to the IGF-1R, thereby triggering the PI3K/Akt signaling cascade required for the differentiation of mesenchymal stem cells into musculoskeletal cells [111,112,113]. Several microRNAs, such as miR-223 and miR-125b, play a role in skeletal muscle homeostasis by modifying IGF2 expression and, thus, its action on myoblast proliferation and differentiation [114,115].
The role of IGF-II in the brain remains to be clearly defined in humans, but studies on rodent models have shown that Igf-II makes a major contribution to the correct functioning of the brain. Igf-II is the most abundant Igf in the adult rodent central nervous system, with particularly high levels in the hippocampus. Moreover, Igf-2R is expressed in almost all regions of the brain, including the hippocampus, olfactory bulb, dentate gyrus, choroid plexus, and the cerebral vascular system. Thus, by regulating Igf-II bioavailability, Igf-2R controls not only neuronal growth and differentiation, but also the mechanisms of neuronal regeneration. Moreover, Igf-I and Igf-II control neuronal survival by inhibiting apoptosis [116]. Studies in mouse models have also revealed a role for Igf-II in the maintenance of adult neural stem-cell niches. Thus, Igf2 deletion results in the differentiation of neural stem cells into neurons, leading to hyposmia, due to an increase in the number of neurons in the olfactory bulb, together with cognitive deficits and increased anxiety [95].
Studies in rats have shown that Igf-II is involved in hippocampus-dependent learning mechanisms. Indeed, Igf-II plays an important role in the consolidation of memory, the retention of information and the prevention of forgetfulness phenomena. These effects are mediated by the Igf2 receptor and lead an increase in the expression of the AMPA receptor subunit GluA1 (ionotropic receptor for glutamate heavily involved in synaptic plasticity) at the synapses, and to activation of the glycogen synthase kinase 3-β enzyme [17,18]. These phenomena participate in the long-term potentiation (LTP) responsible for memory consolidation.
Conversely, several studies in mice have suggested that the deregulation of Igf2 expression may contribute to certain mental illnesses, leading to the hypothesis of a link between decreases in hippocampal Igf-II levels and increases in anxious and depressive behaviors [117,118]. In humans (post-mortem analysis), IGF2 downregulation in the prefrontal cortex is associated with schizophrenic disorders [119,120,121]. Studies on mice and cell models derived from mice have shown that the misregulation of Igf2 is associated with autistic behavior and neurodegenerative diseases, such as Huntington’s disease and Charcot’s disease. In these two neurodegenerative diseases, Igf2 stimulation has a positive effect by preventing the degeneration of motor neurons and promoting their regeneration [122,123,124]. In autistic disorders, Igf2 stimulation leads to a reversal of the clinical signs of autism (restoration of social behavior, abolition of repetitive behaviors, etc.) [125]. Few cognitive studies have been performed in SRS patients with low levels of IGF2 expression, and one study showed that SRS patients did not actually present cognitive deficits relative to a control population, but that they had a smaller frontal and parietal lobe volume in the brain [126].

4. Pathological Aspects

4.1. Silver–Russell Syndrome (SRS)

SRS is a well-recognized imprinting disorder including prenatal and postnatal growth retardation. Clinical diagnosis is currently based on a combination of the characteristic features evaluated with a clinical scoring system (Netchine–Harbison Clinical Scoring System, NHCSS) [127]. Relative macrocephaly at birth is a key criterion for diagnosis and exposes the patient to a high risk of hypoglycemia, which should be carefully monitored. The first international consensus conference on SRS was held in 2015 [76]. A molecular abnormality can be identified in about 60% of patients with a positive clinical diagnosis of SRS (NHCSS > 3). The main molecular causes are low levels of IGF2 expression, due to a loss of methylation of the distal imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 (50%), other rare 11p15.5-related molecular defects, such as IGF2 point mutations affecting the paternal allele, mutations or deletions of HMGA2 and PLAG1, or gain-of-function mutations of CDKN1C [61,128,129,130,131,132]. However, after birth, serum IGF-II levels are within the normal range. Indeed, the IGF-II in the serum, which is principally of hepatic origin, results from biallelic IGF2 expression regulated by the P1 promoter. However, as pointed out above, IGF2 remains imprinted and its expression in other tissues is monoallelic and regulated by the P3 and P4 promoters [130].
SRS patients require multidisciplinary care, as they have many different health issues, including growth failure, severe feeding difficulties in early childhood, gastrointestinal problems, hypoglycemia, puberty and reproductive disturbances, motor and speech delay, sleep apnea and psychosocial challenges [76]. They have also been reported to experience metabolic disturbances in early adulthood, illustrating Barker’s developmental origin of health and diseases theory, according to which, fetal growth retardation triggers long-term health issues [133,134,135], and suggesting that low levels of IGF2 expression during fetal development may have long-term consequences for key physiological processes.

4.2. Temple Syndrome (TS14)

The phenotypes of TS14 and SRS overlap [75,136,137]. TS14 is characterized by pre- and postnatal growth failure, albeit not as severe as in SRS. Fetal growth restriction may be present in up to 75% of cases, a frequency similar to that in SRS. About 50% of TS14 patients have relative macrocephaly at birth. Severe neonatal-onset hypotonia is a prominent feature. Early obesity and precocious puberty onset are typical (86%), often requiring treatment with gonadotropin-releasing hormone analogs [75]. The molecular abnormalities underlying TS14 include hypomethylation of the MEG3/DLK1:IG-DMR in the human 14q32.2 imprinted region. As pointed out above, the downregulation of IGF2 expression in the fibroblasts of TS14 patients may account for the clinical overlap between TS14 and SRS [77].

4.3. Wilms’ Tumors and Beckwith–Wiedemann Syndrome

It has been known for decades that IGF2 is overexpressed in Wilms’ tumors relative to normal postnatal kidney [138]. A loss of heterozygosity (i.e., loss of the maternal allele) or loss of imprinting at the H19/IGF2:IG-DMR (i.e., biallelic expression of IGF2) in Wilms’ tumors was subsequently demonstrated by several teams [139,140]. Finally, in 1995, Taniguchi et al. showed that the loss of IGF2 imprinting in Wilms’ tumors was associated with hypermethylation at the H19/IGF2:IG-DMR, as reported in patients with BWS [141].
Beckwith–Wiedemann syndrome is an overgrowth syndrome. The patients often present with macroglossia, abdominal wall defects, hemihyperplasia, enlarged abdominal organs, and a high risk of embryonal tumors (especially Wilms’ tumors) during early childhood. BWS is mostly due to genetic or epigenetic defects in the 11p15.5 region. The first consensus statement on BWS was released in 2016 [142]. Various molecular defects were identified, including mosaic segmental paternal uniparental isodisomy of 11p15.5 (commonly referred to as segmental upd(11)pat), which can be detected in 20% of patients, and gain of methylation (GOM) at the maternal H19/IGF2:IG-DMR allele, which is present in 5–10% of cases. Both lead to IGF2 overexpression during fetal life. In addition to molecular abnormalities of the IGF2 locus, abnormalities of the CDKN1C locus (i.e., hypomethylation of the KCNQ1OT1:TSS-DMR or maternal loss-of-function mutations of the CDKN1C gene) account for about 75% of the molecular defects. Interestingly, tumor risk is highly correlated with the involvement of the H19/IGF2 locus, as patients with H19/IGF2:IG-DMR GOM or with upd(11)pat have tumor risks of 28% and 16%, respectively, whereas patients with KCNQ1OT1:TSS-DMR LOM have a much lower prevalence of tumors, at 2.6% [143]. IGF2 overexpression, as observed in BWS, is thus responsible for macrosomia, organomegaly and an increase in the risk of embryonal tumors.

5. Conclusions

IGF2 belongs to an imprinted gene network. Its expression is regulated by several upstream factors, and it regulates numerous downstream effectors. The application of new high-throughput technologies (i.e., next-generation sequencing, evaluations of DNA methylation and RNA sequencing) to imprinted disorders in mice or induced pluripotent stem cells and promising dental pluripotent stem cells models should make it possible to decipher more precisely the upstream and downstream actors involved in multiple tissue-specific functions of IGF-II [144,145]. The potential breakthroughs associated with such modeling of IGF2-linked diseases open up new challenges and expand this field of research still further.

Author Contributions

Writing—original draft preparation, C.S., F.B., E.G., M.-L.S., I.N.; Writing—review and editing, C.S., F.B., E.G., M.-L.S., I.N.; visualization, C.S., F.B., E.G., M.-L.S., I.N.; supervision, E.G., F.B., M.-L.S., I.N.; project administration, M.-L.S., I.N. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the ANR-18CE12-022.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

There is no conflict of interest to disclose related with this work for any of the authors.

Nomenclature

IGF-II (IGF-I, IGF-1R, etc.) is used for the protein in humans, and Igf-II (Igf-I, Igf1r, etc.) is used in other species. IGF2 (IGF1, IGF1R, etc.) is used for the gene in humans, and Igf2 (Igf1, Igf1r, etc.) is used in other species.

References

  1. Constância, M.; Hemberger, M.; Hughes, J.; Dean, W.; Ferguson-Smith, A.; Fundele, R.; Stewart, F.; Kelsey, G.; Fowden, A.; Sibley, C.; et al. Placental-Specific IGF-II Is a Major Modulator of Placental and Fetal Growth. Nature 2002, 417, 945–948. [Google Scholar] [CrossRef] [PubMed]
  2. Giabicani, E.; Chantot-Bastaraud, S.; Bonnard, A.; Rachid, M.; Whalen, S.; Netchine, I.; Brioude, F. Roles of Type 1 Insulin-Like Growth Factor (IGF) Receptor and IGF-II in Growth Regulation: Evidence from a Patient Carrying Both an 11p Paternal Duplication and 15q Deletion. Front. Endocrinol. 2019, 10, 263. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Yu, H.; Berkel, H. Insulin-like Growth Factors and Cancer. J. State Med. Soc. 1999, 151, 218–223. [Google Scholar]
  4. Hakuno, F.; Takahashi, S.-I. IGF1 Receptor Signaling Pathways. J. Mol. Endocrinol. 2018, 61, T69–T86. [Google Scholar] [CrossRef] [Green Version]
  5. Bergman, D.; Halje, M.; Nordin, M.; Engström, W. Insulin-Like Growth Factor 2 in Development and Disease: A Mini-Review. Gerontology 2013, 59, 240–249. [Google Scholar] [CrossRef]
  6. Chao, W.; D’Amore, P.A. IGF2: Epigenetic Regulation and Role in Development and Disease. Cytokine Growth Factor Rev. 2008, 19, 111–120. [Google Scholar] [CrossRef] [Green Version]
  7. Henderson, S.T.; Brierley, G.V.; Surinya, K.H.; Priebe, I.K.; Catcheside, D.E.A.; Wallace, J.C.; Forbes, B.E.; Cosgrove, L.J. Delineation of the IGF-II C Domain Elements Involved in Binding and Activation of the IR-A, IR-B and IGF-IR. Growth Horm. IGF Res. 2015, 25, 20–27. [Google Scholar] [CrossRef]
  8. LeRoith, D.; Werner, H.; Beitner-Johnson, D.; Roberts, C.T. Molecular and Cellular Aspects of the Insulin-like Growth Factor I Receptor. Endocr. Rev. 1995, 16, 143–163. [Google Scholar] [CrossRef]
  9. Frasca, F.; Pandini, G.; Scalia, P.; Sciacca, L.; Mineo, R.; Costantino, A.; Goldfine, I.D.; Belfiore, A.; Vigneri, R. Insulin Receptor Isoform A, a Newly Recognized, High-Affinity Insulin-like Growth Factor II Receptor in Fetal and Cancer Cells. Mol. Cell. Biol. 1999, 19, 3278–3288. [Google Scholar] [CrossRef] [Green Version]
  10. Andersen, M.; Nørgaard-Pedersen, D.; Brandt, J.; Pettersson, I.; Slaaby, R. IGF1 and IGF2 Specificities to the Two Insulin Receptor Isoforms Are Determined by Insulin Receptor Amino Acid 718. PLoS ONE 2017, 12, e0178885. [Google Scholar] [CrossRef] [Green Version]
  11. Tong, P.Y.; Tollefsen, S.E.; Kornfeld, S. The Cation-Independent Mannose 6-Phosphate Receptor Binds Insulin-like Growth Factor II. J. Biol. Chem. 1988, 263, 2585–2588. [Google Scholar] [CrossRef]
  12. Brown, J.; Delaine, C.; Zaccheo, O.J.; Siebold, C.; Gilbert, R.J.; van Boxel, G.; Denley, A.; Wallace, J.C.; Hassan, A.B.; Forbes, B.E.; et al. Structure and Functional Analysis of the IGF-II/IGF2R Interaction. EMBO J. 2008, 27, 265–276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Morgan, D.O.; Edman, J.C.; Standring, D.N.; Fried, V.A.; Smith, M.C.; Roth, R.A.; Rutter, W.J. Insulin-like Growth Factor II Receptor as a Multifunctional Binding Protein. Nature 1987, 329, 301–307. [Google Scholar] [CrossRef] [PubMed]
  14. Clemmons, D.R. Structural and Functional Analysis of Insulin-like Growth Factors. Br. Med. Bull. 1989, 45, 465–480. [Google Scholar] [CrossRef] [PubMed]
  15. Oka, Y.; Rozek, L.M.; Czech, M.P. Direct Demonstration of Rapid Insulin-like Growth Factor II Receptor Internalization and Recycling in Rat Adipocytes. Insulin Stimulates 125I-Insulin-like Growth Factor II Degradation by Modulating the IGF-II Receptor Recycling Process. J. Biol. Chem. 1985, 260, 9435–9442. [Google Scholar] [CrossRef]
  16. Yu, X.-W.; Pandey, K.; Katzman, A.C.; Alberini, C.M. A Role for CIM6P/IGF2 Receptor in Memory Consolidation and Enhancement. eLife 2020, 9, e54781. [Google Scholar] [CrossRef]
  17. Stern, S.A.; Chen, D.Y.; Alberini, C.M. The Effect of Insulin and Insulin-like Growth Factors on Hippocampus- and Amygdala-Dependent Long-Term Memory Formation. Learn. Mem. 2014, 21, 556–563. [Google Scholar] [CrossRef] [Green Version]
  18. Chen, D.Y.; Stern, S.A.; Garcia-Osta, A.; Saunier-Rebori, B.; Pollonini, G.; Bambah-Mukku, D.; Blitzer, R.D.; Alberini, C.M. A Critical Role for IGF-II in Memory Consolidation and Enhancement. Nature 2011, 469, 491–497. [Google Scholar] [CrossRef]
  19. Oh, Y.; Müller, H.L.; Lee, D.Y.; Fielder, P.J.; Rosenfeld, R.G. Characterization of the Affinities of Insulin-like Growth Factor (IGF)-Binding Proteins 1-4 for IGF-I, IGF-II, IGF-I/Insulin Hybrid, and IGF-I Analogs. Endocrinology 1993, 132, 1337–1344. [Google Scholar] [CrossRef]
  20. Jones, J.I.; Clemmons, D.R. Insulin-like Growth Factors and Their Binding Proteins: Biological Actions. Endocr. Rev. 1995, 16, 3–34. [Google Scholar] [CrossRef]
  21. Clemmons, D.R. Role of IGF-Binding Proteins in Regulating IGF Responses to Changes in Metabolism. J. Mol. Endocrinol. 2018, 61, T139–T169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Forbes, B.E.; McCarthy, P.; Norton, R.S. Insulin-Like Growth Factor Binding Proteins: A Structural Perspective. Front. Endocrin. 2012, 3, 38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Bach, L.A. 40 Years of IGF1: IGF-Binding Proteins. J. Mol. Endocrinol. 2018, 61, T11–T28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Baxter, R.C. Characterization of the Acid-Labile Subunit of the Growth Hormone-Dependent Insulin-like Growth Factor Binding Protein Complex. J. Clin. Endocrinol. Metab. 1988, 67, 265–272. [Google Scholar] [CrossRef] [PubMed]
  25. Frystyk, J.; Teran, E.; Gude, M.F.; Bjerre, M.; Hjortebjerg, R. Pregnancy-Associated Plasma Proteins and Stanniocalcin-2—Novel Players Controlling IGF-I Physiology. Growth Horm. IGF Res. 2020, 53–54, 101330. [Google Scholar] [CrossRef] [PubMed]
  26. Firth, S.M.; Baxter, R.C. Cellular Actions of the Insulin-Like Growth Factor Binding Proteins. Endocr. Rev. 2002, 23, 824–854. [Google Scholar] [CrossRef]
  27. Blat, C.; Villaudy, J.; Binoux, M. In Vivo Proteolysis of Serum Insulin-like Growth Factor (IGF) Binding Protein-3 Results in Increased Availability of IGF to Target Cells. J. Clin. Investig. 1994, 93, 2286–2290. [Google Scholar] [CrossRef] [Green Version]
  28. Lawrence, J.B.; Oxvig, C.; Overgaard, M.T.; Sottrup-Jensen, L.; Gleich, G.J.; Hays, L.G.; Yates, J.R.; Conover, C.A. The Insulin-like Growth Factor (IGF)-Dependent IGF Binding Protein-4 Protease Secreted by Human Fibroblasts Is Pregnancy-Associated Plasma Protein-A. Proc. Natl. Acad. Sci. USA 1999, 96, 3149–3153. [Google Scholar] [CrossRef] [Green Version]
  29. Oxvig, C. The Role of PAPP-A in the IGF System: Location, Location, Location. J. Cell Commun. Signal. 2015, 9, 177–187. [Google Scholar] [CrossRef] [Green Version]
  30. Barrios, V.; Chowen, J.A.; Martín-Rivada, Á.; Guerra-Cantera, S.; Pozo, J.; Yakar, S.; Rosenfeld, R.G.; Pérez-Jurado, L.A.; Suárez, J.; Argente, J. Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease. Cells 2021, 10, 3576. [Google Scholar] [CrossRef]
  31. Dauber, A.; Muñoz-Calvo, M.T.; Barrios, V.; Domené, H.M.; Kloverpris, S.; Serra-Juhé, C.; Desikan, V.; Pozo, J.; Muzumdar, R.; Martos-Moreno, G.Á.; et al. Mutations in Pregnancy-Associated Plasma Protein A2 Cause Short Stature Due to Low IGF-I Availability. EMBO Mol. Med. 2016, 8, 363–374. [Google Scholar] [CrossRef] [PubMed]
  32. Han, V.K.; D’Ercole, A.J.; Lund, P.K. Cellular Localization of Somatomedin (Insulin-like Growth Factor) Messenger RNA in the Human Fetus. Science 1987, 236, 193–197. [Google Scholar] [CrossRef] [PubMed]
  33. Sferruzzi-Perri, A.N.; Sandovici, I.; Constancia, M.; Fowden, A.L. Placental Phenotype and the Insulin-like Growth Factors: Resource Allocation to Fetal Growth. J. Physiol. 2017, 595, 5057–5093. [Google Scholar] [CrossRef] [PubMed]
  34. Vu, T.H.; Hoffman, A.R. Promoter-Specific Imprinting of the Human Insulin-like Growth Factor-II Gene. Nature 1994, 371, 714–717. [Google Scholar] [CrossRef]
  35. Toogood, A.A.; Jones, J.; O’Neill, P.A.; Thorner, M.O.; Shalet, S.M. The Diagnosis of Severe Growth Hormone Deficiency in Elderly Patients with Hypothalamic-Pituitary Disease: Diagnosis of GH Deficiency in the Elderly. Clin. Endocrinol. 1998, 48, 569–576. [Google Scholar] [CrossRef]
  36. DeChiara, T.M.; Efstratiadis, A.; Robertsen, E.J. A Growth-Deficiency Phenotype in Heterozygous Mice Carrying an Insulin-like Growth Factor II Gene Disrupted by Targeting. Nature 1990, 345, 78–80. [Google Scholar] [CrossRef]
  37. DeChiara, T.M.; Robertson, E.J.; Efstratiadis, A. Parental Imprinting of the Mouse Insulin-like Growth Factor II Gene. Cell 1991, 64, 849–859. [Google Scholar] [CrossRef]
  38. Baral, K.; Rotwein, P. The Insulin-like Growth Factor 2 Gene in Mammals: Organizational Complexity within a Conserved Locus. PLoS ONE 2019, 14, e0219155. [Google Scholar] [CrossRef]
  39. De Pagter-Holthuizen, P.; Jansen, M.; van Schaik, F.M.A.; van der Kammen, R.; Oosterwijk, C.; Van den Brande, J.L.; Sussenbach, J.S. The Human Insulin-like Growth Factor II Gene Contains Two Development-Specific Promoters. FEBS Lett. 1987, 214, 259–264. [Google Scholar] [CrossRef] [Green Version]
  40. Zapf, J.; Futo, E.; Peter, M.; Froesch, E.R. Can “Big” Insulin-like Growth Factor II in Serum of Tumor Patients Account for the Development of Extrapancreatic Tumor Hypoglycemia? J. Clin. Investig. 1992, 90, 2574–2584. [Google Scholar] [CrossRef] [Green Version]
  41. Rotwein, P. Large-Scale Analysis of Variation in the Insulin-like Growth Factor Family in Humans Reveals Rare Disease Links and Common Polymorphisms. J. Biol. Chem. 2017, 292, 9252–9261. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Moore, T.; Constancia, M.; Zubair, M.; Bailleul, B.; Feil, R.; Sasaki, H.; Reik, W. Multiple Imprinted Sense and Antisense Transcripts, Differential Methylation and Tandem Repeats in a Putative Imprinting Control Region Upstream of Mouse Igf2. Proc. Natl. Acad. Sci. USA 1997, 94, 12509–12514. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Khosla, S.; Aitchison, A.; Gregory, R.; Allen, N.D.; Feil, R. Parental Allele-Specific Chromatin Configuration in a Boundary-Imprinting-Control Element Upstream of the Mouse H19 Gene. Mol. Cell. Biol. 1999, 19, 2556–2566. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Phillips, J.E.; Corces, V.G. CTCF: Master Weaver of the Genome. Cell 2009, 137, 1194–1211. [Google Scholar] [CrossRef] [Green Version]
  45. Takai, D.; Gonzales, F.A.; Tsai, Y.C.; Thayer, M.J.; Jones, P.A. Large Scale Mapping of Methylcytosines in CTCF-Binding Sites in the Human H19 Promoter and Aberrant Hypomethylation in Human Bladder Cancer. Hum. Mol. Genet. 2001, 10, 2619–2626. [Google Scholar] [CrossRef] [Green Version]
  46. Abi Habib, W.; Azzi, S.; Brioude, F.; Steunou, V.; Thibaud, N.; Das Neves, C.; Le Jule, M.; Chantot-Bastaraud, S.; Keren, B.; Lyonnet, S.; et al. Extensive Investigation of the IGF2/H19 Imprinting Control Region Reveals Novel OCT4/SOX2 Binding Site Defects Associated with Specific Methylation Patterns in Beckwith-Wiedemann Syndrome. Hum. Mol. Genet. 2014, 23, 5763–5773. [Google Scholar] [CrossRef] [Green Version]
  47. Kurukuti, S.; Tiwari, V.K.; Tavoosidana, G.; Pugacheva, E.; Murrell, A.; Zhao, Z.; Lobanenkov, V.; Reik, W.; Ohlsson, R. CTCF Binding at the H19 Imprinting Control Region Mediates Maternally Inherited Higher-Order Chromatin Conformation to Restrict Enhancer Access to Igf2. Proc. Natl. Acad. Sci. USA 2006, 103, 10684–10689. [Google Scholar] [CrossRef] [Green Version]
  48. Demars, J.; Shmela, M.E.; Rossignol, S.; Okabe, J.; Netchine, I.; Azzi, S.; Cabrol, S.; Le Caignec, C.; David, A.; Le Bouc, Y.; et al. Analysis of the IGF2/H19 Imprinting Control Region Uncovers New Genetic Defects, Including Mutations of OCT-Binding Sequences, in Patients with 11p15 Fetal Growth Disorders. Hum. Mol. Genet. 2010, 19, 803–814. [Google Scholar] [CrossRef] [Green Version]
  49. Weth, O.; Renkawitz, R. CTCF Function Is Modulated by Neighboring DNA Binding Factors. Biochem. Cell Biol. 2011, 89, 459–468. [Google Scholar] [CrossRef]
  50. Zimmerman, D.L.; Boddy, C.S.; Schoenherr, C.S. Oct4/Sox2 Binding Sites Contribute to Maintaining Hypomethylation of the Maternal Igf2/H19 Imprinting Control Region. PLoS ONE 2013, 8, e81962. [Google Scholar] [CrossRef] [Green Version]
  51. Sakaguchi, R.; Okamura, E.; Matsuzaki, H.; Fukamizu, A.; Tanimoto, K. Sox-Oct Motifs Contribute to Maintenance of the Unmethylated H19 ICR in YAC Transgenic Mice. Hum. Mol. Genet. 2013, 22, 4627–4637. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Abi Habib, W.; Brioude, F.; Azzi, S.; Salem, J.; Das Neves, C.; Personnier, C.; Chantot-Bastaraud, S.; Keren, B.; Le Bouc, Y.; Harbison, M.D.; et al. 11p15 ICR1 Partial Deletions Associated with IGF2/H19 DMR Hypomethylation and Silver-Russell Syndrome. Hum. Mutat. 2017, 38, 105–111. [Google Scholar] [CrossRef] [PubMed]
  53. Quenneville, S.; Verde, G.; Corsinotti, A.; Kapopoulou, A.; Jakobsson, J.; Offner, S.; Baglivo, I.; Pedone, P.V.; Grimaldi, G.; Riccio, A.; et al. In Embryonic Stem Cells, ZFP57/KAP1 Recognize a Methylated Hexanucleotide to Affect Chromatin and DNA Methylation of Imprinting Control Regions. Mol. Cell 2011, 44, 361–372. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Takahashi, N.; Coluccio, A.; Thorball, C.W.; Planet, E.; Shi, H.; Offner, S.; Turelli, P.; Imbeault, M.; Ferguson-Smith, A.C.; Trono, D. ZNF445 Is a Primary Regulator of Genomic Imprinting. Genes Dev. 2019, 33, 49–54. [Google Scholar] [CrossRef] [Green Version]
  55. Monk, D.; Sanches, R.; Arnaud, P.; Apostolidou, S.; Hills, F.A.; Abu-Amero, S.; Murrell, A.; Friess, H.; Reik, W.; Stanier, P.; et al. Imprinting of IGF2 P0 Transcript and Novel Alternatively Spliced INS-IGF2 Isoforms Show Differences between Mouse and Human. Hum. Mol. Genet. 2006, 15, 1259–1269. [Google Scholar] [CrossRef] [Green Version]
  56. Dekker, J.; Rippe, K.; Dekker, M.; Kleckner, N. Capturing Chromosome Conformation. Science 2002, 295, 1306–1311. [Google Scholar] [CrossRef] [Green Version]
  57. Arney, K.L. H19 and Igf2—Enhancing the Confusion? Trends Genet. 2003, 19, 17–23. [Google Scholar] [CrossRef]
  58. Yoon, Y.S.; Jeong, S.; Rong, Q.; Park, K.-Y.; Chung, J.H.; Pfeifer, K. Analysis of the H19ICR Insulator. Mol. Cell. Biol. 2007, 27, 3499–3510. [Google Scholar] [CrossRef] [Green Version]
  59. Llères, D.; Moindrot, B.; Pathak, R.; Piras, V.; Matelot, M.; Pignard, B.; Marchand, A.; Poncelet, M.; Perrin, A.; Tellier, V.; et al. CTCF Modulates Allele-Specific Sub-TAD Organization and Imprinted Gene Activity at the Mouse Dlk1-Dio3 and Igf2-H19 Domains. Genome Biol. 2019, 20, 272. [Google Scholar] [CrossRef] [Green Version]
  60. Rovina, D.; La Vecchia, M.; Cortesi, A.; Fontana, L.; Pesant, M.; Maitz, S.; Tabano, S.; Bodega, B.; Miozzo, M.; Sirchia, S.M. Profound Alterations of the Chromatin Architecture at Chromosome 11p15.5 in Cells from Beckwith-Wiedemann and Silver-Russell Syndromes Patients. Sci. Rep. 2020, 10, 8275. [Google Scholar] [CrossRef]
  61. Abi Habib, W.; Brioude, F.; Edouard, T.; Bennett, J.T.; Lienhardt-Roussie, A.; Tixier, F.; Salem, J.; Yuen, T.; Azzi, S.; Le Bouc, Y.; et al. Genetic Disruption of the Oncogenic HMGA2-PLAG1-IGF2 Pathway Causes Fetal Growth Restriction. Genet. Med. 2018, 20, 250–258. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Voz, M.L.; Agten, N.S.; Van de Ven, W.J.; Kas, K. PLAG1, the Main Translocation Target in Pleomorphic Adenoma of the Salivary Glands, Is a Positive Regulator of IGF-II. Cancer Res. 2000, 60, 106–113. [Google Scholar] [PubMed]
  63. Van Dyck, F.; Declercq, J.; Braem, C.V.; Van de Ven, W.J.M. PLAG1, the Prototype of the PLAG Gene Family: Versatility in Tumour Development. Int. J. Oncol. 2007, 30, 765–774. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Hensen, K.; Braem, C.; Declercq, J.; Van Dyck, F.; Dewerchin, M.; Fiette, L.; Denef, C.; Van de Ven, W.J.M. Targeted Disruption of the Murine Plag1 Proto-Oncogene Causes Growth Retardation and Reduced Fertility. Dev. Growth Differ. 2004, 46, 459–470. [Google Scholar] [CrossRef]
  65. Manfioletti, G.; Giancotti, V.; Bandiera, A.; Buratti, E.; Sautière, P.; Cary, P.; Crane-Robinson, C.; Coles, B.; Goodwin, G.H. CDNA Cloning of the HMGI-C Phosphoprotein, a Nuclear Protein Associated with Neoplastic and Undifferentiated Phenotypes. Nucleic Acids Res. 1991, 19, 6793–6797. [Google Scholar] [CrossRef]
  66. Zhou, X.; Benson, K.F.; Ashar, H.R.; Chada, K. Mutation Responsible for the Mouse Pygmy Phenotype in the Developmentally Regulated Factor HMGI-C. Nature 1995, 376, 771–774. [Google Scholar] [CrossRef]
  67. Klemke, M.; Müller, M.H.; Wosniok, W.; Markowski, D.N.; Nimzyk, R.; Helmke, B.M.; Bullerdiek, J. Correlated Expression of HMGA2 and PLAG1 in Thyroid Tumors, Uterine Leiomyomas and Experimental Models. PLoS ONE 2014, 9, e88126. [Google Scholar] [CrossRef]
  68. Astuti, D.; Morris, M.R.; Cooper, W.N.; Staals, R.H.J.; Wake, N.C.; Fews, G.A.; Gill, H.; Gentle, D.; Shuib, S.; Ricketts, C.J.; et al. Germline Mutations in DIS3L2 Cause the Perlman Syndrome of Overgrowth and Wilms Tumor Susceptibility. Nat. Genet. 2012, 44, 277–284. [Google Scholar] [CrossRef]
  69. Hunter, R.W.; Liu, Y.; Manjunath, H.; Acharya, A.; Jones, B.T.; Zhang, H.; Chen, B.; Ramalingam, H.; Hammer, R.E.; Xie, Y.; et al. Loss of Dis3l2 Partially Phenocopies Perlman Syndrome in Mice and Results in Up-Regulation of Igf2 in Nephron Progenitor Cells. Genes Dev. 2018, 32, 903–908. [Google Scholar] [CrossRef] [Green Version]
  70. Varrault, A.; Gueydan, C.; Delalbre, A.; Bellmann, A.; Houssami, S.; Aknin, C.; Severac, D.; Chotard, L.; Kahli, M.; Le Digarcher, A.; et al. Zac1 Regulates an Imprinted Gene Network Critically Involved in the Control of Embryonic Growth. Dev. Cell 2006, 11, 711–722. [Google Scholar] [CrossRef]
  71. Gabory, A.; Ripoche, M.-A.; Le Digarcher, A.; Watrin, F.; Ziyyat, A.; Forné, T.; Jammes, H.; Ainscough, J.F.X.; Surani, M.A.; Journot, L.; et al. H19 Acts as a Trans Regulator of the Imprinted Gene Network Controlling Growth in Mice. Development 2009, 136, 3413–3421. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Al Adhami, H.; Evano, B.; Le Digarcher, A.; Gueydan, C.; Dubois, E.; Parrinello, H.; Dantec, C.; Bouschet, T.; Varrault, A.; Journot, L. A Systems-Level Approach to Parental Genomic Imprinting: The Imprinted Gene Network Includes Extracellular Matrix Genes and Regulates Cell Cycle Exit and Differentiation. Genome Res. 2015, 25, 353–367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Whipple, A.J.; Breton-Provencher, V.; Jacobs, H.N.; Chitta, U.K.; Sur, M.; Sharp, P.A. Imprinted Maternally Expressed MicroRNAs Antagonize Paternally Driven Gene Programs in Neurons. Mol. Cell 2020, 78, 85–95. [Google Scholar] [CrossRef] [PubMed]
  74. Eggermann, T.; Davies, J.H.; Tauber, M.; van den Akker, E.; Hokken-Koelega, A.; Johansson, G.; Netchine, I. Growth Restriction and Genomic Imprinting-Overlapping Phenotypes Support the Concept of an Imprinting Network. Genes 2021, 12, 585. [Google Scholar] [CrossRef] [PubMed]
  75. Geoffron, S.; Abi Habib, W.; Chantot-Bastaraud, S.; Dubern, B.; Steunou, V.; Azzi, S.; Afenjar, A.; Busa, T.; Pinheiro Canton, A.; Chalouhi, C.; et al. Chromosome 14q32.2 Imprinted Region Disruption as an Alternative Molecular Diagnosis of Silver-Russell Syndrome. J. Clin. Endocrinol. Metab. 2018, 103, 2436–2446. [Google Scholar] [CrossRef] [Green Version]
  76. Wakeling, E.L.; Brioude, F.; Lokulo-Sodipe, O.; O’Connell, S.M.; Salem, J.; Bliek, J.; Canton, A.P.M.; Chrzanowska, K.H.; Davies, J.H.; Dias, R.P.; et al. Diagnosis and Management of Silver-Russell Syndrome: First International Consensus Statement. Nat. Rev. Endocrinol. 2017, 13, 105–124. [Google Scholar] [CrossRef]
  77. Abi Habib, W.; Brioude, F.; Azzi, S.; Rossignol, S.; Linglart, A.; Sobrier, M.-L.; Giabicani, É.; Steunou, V.; Harbison, M.D.; Le Bouc, Y.; et al. Transcriptional Profiling at the DLK1/MEG3 Domain Explains Clinical Overlap between Imprinting Disorders. Sci. Adv. 2019, 5, eaau9425. [Google Scholar] [CrossRef] [Green Version]
  78. Ishida, M.; Ohashi, S.; Kizaki, Y.; Naito, J.; Horiguchi, K.; Harigaya, T. Expression Profiling of Mouse Placental Lactogen II and Its Correlative Genes Using a CDNA Microarray Analysis in the Developmental Mouse Placenta. J. Reprod. Dev. 2007, 53, 69–76. [Google Scholar] [CrossRef] [Green Version]
  79. Coan, P.M.; Fowden, A.L.; Constancia, M.; Ferguson-Smith, A.C.; Burton, G.J.; Sibley, C.P. Disproportional Effects of Igf2 Knockout on Placental Morphology and Diffusional Exchange Characteristics in the Mouse. J. Physiol. 2008, 586, 5023–5032. [Google Scholar] [CrossRef]
  80. Sibley, C.P.; Coan, P.M.; Ferguson-Smith, A.C.; Dean, W.; Hughes, J.; Smith, P.; Reik, W.; Burton, G.J.; Fowden, A.L.; Constância, M. Placental-Specific Insulin-like Growth Factor 2 (Igf2) Regulates the Diffusional Exchange Characteristics of the Mouse Placenta. Proc. Natl. Acad. Sci. USA 2004, 101, 8204–8208. [Google Scholar] [CrossRef] [Green Version]
  81. Sandovici, I.; Georgopoulou, A.; Pérez-García, V.; Hufnagel, A.; López-Tello, J.; Lam, B.Y.H.; Schiefer, S.N.; Gaudreau, C.; Santos, F.; Hoelle, K.; et al. The Imprinted Igf2-Igf2r Axis Is Critical for Matching Placental Microvasculature Expansion to Fetal Growth. Dev. Cell 2022, 57, 63–79. [Google Scholar] [CrossRef] [PubMed]
  82. Schmidt, A.; Morales-Prieto, D.M.; Pastuschek, J.; Fröhlich, K.; Markert, U.R. Only Humans Have Human Placentas: Molecular Differences between Mice and Humans. J. Reprod. Immunol. 2015, 108, 65–71. [Google Scholar] [CrossRef] [PubMed]
  83. Malassiné, A.; Frendo, J.L.; Evain-Brion, D. A Comparison of Placental Development and Endocrine Functions between the Human and Mouse Model. Hum. Reprod. Update 2003, 9, 531–539. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Yamazawa, K.; Kagami, M.; Nagai, T.; Kondoh, T.; Onigata, K.; Maeyama, K.; Hasegawa, T.; Hasegawa, Y.; Yamazaki, T.; Mizuno, S.; et al. Molecular and Clinical Findings and Their Correlations in Silver-Russell Syndrome: Implications for a Positive Role of IGF2 in Growth Determination and Differential Imprinting Regulation of the IGF2–H19 Domain in Bodies and Placentas. J. Mol. Med. 2008, 86, 1171–1181. [Google Scholar] [CrossRef]
  85. Harris, L.K.; Crocker, I.P.; Baker, P.N.; Aplin, J.D.; Westwood, M. IGF2 Actions on Trophoblast in Human Placenta Are Regulated by the Insulin-like Growth Factor 2 Receptor, Which Can Function as Both a Signaling and Clearance Receptor. Biol. Reprod. 2011, 84, 440–446. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Gaillot-Durand, L.; Brioude, F.; Beneteau, C.; Le Breton, F.; Massardier, J.; Michon, L.; Devouassoux-Shisheboran, M.; Allias, F. Placental Pathology in Beckwith-Wiedemann Syndrome According to Genotype/Epigenotype Subgroups. Fetal Pediatr. Pathol. 2018, 37, 387–399. [Google Scholar] [CrossRef]
  87. Armes, J.E.; McGown, I.; Williams, M.; Broomfield, A.; Gough, K.; Lehane, F.; Lourie, R. The Placenta in Beckwith-Wiedemann Syndrome: Genotype-Phenotype Associations, Excessive Extravillous Trophoblast and Placental Mesenchymal Dysplasia. Pathology 2012, 44, 519–527. [Google Scholar] [CrossRef]
  88. Morali, O.G.; Jouneau, A.; McLaughlin, K.J.; Thiery, J.P.; Larue, L. IGF-II Promotes Mesoderm Formation. Dev. Biol. 2000, 227, 133–145. [Google Scholar] [CrossRef] [Green Version]
  89. Li, X.; Cui, H.; Sandstedt, B.; Nordlinder, H.; Larsson, E.; Ekström, T.J. Expression Levels of the Insulin-like Growth Factor-II Gene (IGF2) in the Human Liver: Developmental Relationships of the Four Promoters. J. Endocrinol. 1996, 149, 117–124. [Google Scholar] [CrossRef]
  90. Barton, S.C.; Surani, M.A.; Norris, M.L. Role of Paternal and Maternal Genomes in Mouse Development. Nature 1984, 311, 374–376. [Google Scholar] [CrossRef]
  91. McGrath, J.; Solter, D. Inability of Mouse Blastomere Nuclei Transferred to Enucleated Zygotes to Support Development in Vitro. Science 1984, 226, 1317–1319. [Google Scholar] [CrossRef] [PubMed]
  92. Lui, J.C.; Baron, J. Evidence That Igf2 Down-Regulation in Postnatal Tissues and up-Regulation in Malignancies Is Driven by Transcription Factor E2f3. Proc. Natl. Acad. Sci. USA 2013, 110, 6181–6186. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Pascual-Lucas, M.; Viana da Silva, S.; Di Scala, M.; Garcia-Barroso, C.; González-Aseguinolaza, G.; Mulle, C.; Alberini, C.M.; Cuadrado-Tejedor, M.; Garcia-Osta, A. Insulin-like Growth Factor 2 Reverses Memory and Synaptic Deficits in APP Transgenic Mice. EMBO Mol. Med. 2014, 6, 1246–1262. [Google Scholar] [CrossRef] [PubMed]
  94. Schmeisser, M.J.; Baumann, B.; Johannsen, S.; Vindedal, G.F.; Jensen, V.; Hvalby, Ø.C.; Sprengel, R.; Seither, J.; Maqbool, A.; Magnutzki, A.; et al. IκB Kinase/Nuclear Factor ΚB-Dependent Insulin-like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling. J. Neurosci. 2012, 32, 5688–5703. [Google Scholar] [CrossRef]
  95. Ziegler, A.N.; Feng, Q.; Chidambaram, S.; Testai, J.M.; Kumari, E.; Rothbard, D.E.; Constancia, M.; Sandovici, I.; Cominski, T.; Pang, K.; et al. Insulin-like Growth Factor II: An Essential Adult Stem Cell Niche Constituent in Brain and Intestine. Stem Cell Rep. 2019, 12, 816–830. [Google Scholar] [CrossRef] [Green Version]
  96. Rotwein, P. The Complex Genetics of Human Insulin-like Growth Factor 2 Are Not Reflected in Public Databases. J. Biol. Chem. 2018, 293, 4324–4333. [Google Scholar] [CrossRef] [Green Version]
  97. van Dijk, M.A.; Holthuizen, P.E.; Sussenbach, J.S. Elements Required for Activation of the Major Promoter of the Human Insulin-like Growth Factor II Gene. Mol. Cell. Endocrinol. 1992, 88, 175–185. [Google Scholar] [CrossRef]
  98. Jin, I.H.; Sinha, G.; Yballe, C.; Vu, T.H.; Hoffman, A.R. The Human Insulin-like Growth Factor-II Promoter P1 Is Not Restricted to Liver: Evidence for Expression of P1 in Other Tissues and for a Homologous Promoter in Baboon Liver. Horm. Metab. Res. 1995, 27, 447–449. [Google Scholar] [CrossRef]
  99. Uchimura, T.; Hollander, J.M.; Nakamura, D.S.; Liu, Z.; Rosen, C.J.; Georgakoudi, I.; Zeng, L. An Essential Role for IGF2 in Cartilage Development and Glucose Metabolism during Postnatal Long Bone Growth. Development 2017, 144, 3533–3546. [Google Scholar] [CrossRef] [Green Version]
  100. Chen, L.; Jiang, W.; Huang, J.; He, B.-C.; Zuo, G.-W.; Zhang, W.; Luo, Q.; Shi, Q.; Zhang, B.-Q.; Wagner, E.R.; et al. Insulin-like Growth Factor 2 (IGF-2) Potentiates BMP-9-Induced Osteogenic Differentiation and Bone Formation. J. Bone Miner. Res. 2010, 25, 2447–2459. [Google Scholar] [CrossRef] [Green Version]
  101. Hamamura, K.; Zhang, P.; Yokota, H. IGF2-Driven PI3 Kinase and TGFbeta Signaling Pathways in Chondrogenesis. Cell Biol. Int. 2008, 32, 1238–1246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Piecewicz, S.M.; Pandey, A.; Roy, B.; Xiang, S.H.; Zetter, B.R.; Sengupta, S. Insulin-like Growth Factors Promote Vasculogenesis in Embryonic Stem Cells. PLoS ONE 2012, 7, e32191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Dallinga, M.G.; Yetkin-Arik, B.; Kayser, R.P.; Vogels, I.M.C.; Nowak-Sliwinska, P.; Griffioen, A.W.; van Noorden, C.J.F.; Klaassen, I.; Schlingemann, R.O. IGF2 and IGF1R Identified as Novel Tip Cell Genes in Primary Microvascular Endothelial Cell Monolayers. Angiogenesis 2018, 21, 823–836. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Dallinga, M.G.; Habani, Y.I.; Kayser, R.P.; Van Noorden, C.J.F.; Klaassen, I.; Schlingemann, R.O. IGF-Binding Proteins 3 and 4 Are Regulators of Sprouting Angiogenesis. Mol. Biol. Rep. 2020, 47, 2561–2572. [Google Scholar] [CrossRef] [Green Version]
  105. Alfares, M.N.; Perks, C.M.; Hamilton-Shield, J.P.; Holly, J.M.P. Insulin-like Growth Factor-II in Adipocyte Regulation: Depot-Specific Actions Suggest a Potential Role Limiting Excess Visceral Adiposity. Am. J. Physiol.-Endocrinol. Metab. 2018, 315, E1098–E1107. [Google Scholar] [CrossRef]
  106. Liang, L.; Guo, W.H.; Esquiliano, D.R.; Asai, M.; Rodriguez, S.; Giraud, J.; Kushner, J.A.; White, M.F.; Lopez, M.F. Insulin-Like Growth Factor 2 and the Insulin Receptor, But Not Insulin, Regulate Fetal Hepatic Glycogen Synthesis. Endocrinology 2010, 151, 741–747. [Google Scholar] [CrossRef] [Green Version]
  107. Wang, M.-J.; Chen, F.; Liu, Q.-G.; Liu, C.-C.; Yao, H.; Yu, B.; Zhang, H.-B.; Yan, H.-X.; Ye, Y.; Chen, T.; et al. Insulin-like Growth Factor 2 Is a Key Mitogen Driving Liver Repopulation in Mice. Cell Death Dis. 2018, 9, 26. [Google Scholar] [CrossRef] [Green Version]
  108. Portela-Gomes, G.M.; Höög, A. Insulin-like Growth Factor II in Human Fetal Pancreas and Its Co-Localization with the Major Islet Hormones: Comparison with Adult Pancreas. J. Endocrinol. 2000, 165, 245–251. [Google Scholar] [CrossRef] [Green Version]
  109. Hammerle, C.M.; Sandovici, I.; Brierley, G.V.; Smith, N.M.; Zimmer, W.E.; Zvetkova, I.; Prosser, H.M.; Sekita, Y.; Lam, B.Y.H.; Ma, M.; et al. Mesenchyme-Derived IGF2 Is a Major Paracrine Regulator of Pancreatic Growth and Function. PLoS Genet. 2020, 16, e1009069. [Google Scholar] [CrossRef]
  110. Sandovici, I.; Hammerle, C.M.; Virtue, S.; Vivas-Garcia, Y.; Izquierdo-Lahuerta, A.; Ozanne, S.E.; Vidal-Puig, A.; Medina-Gómez, G.; Constância, M. Autocrine IGF2 Programmes β-Cell Plasticity under Conditions of Increased Metabolic Demand. Sci. Rep. 2021, 11, 7717. [Google Scholar] [CrossRef]
  111. Wilson, E.M.; Rotwein, P. Control of MyoD Function during Initiation of Muscle Differentiation by an Autocrine Signaling Pathway Activated by Insulin-like Growth Factor-II. J. Biol. Chem. 2006, 281, 29962–29971. [Google Scholar] [CrossRef] [Green Version]
  112. Aboalola, D.; Han, V.K.M. Different Effects of Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor-2 on Myogenic Differentiation of Human Mesenchymal Stem Cells. Stem Cells Int. 2017, 2017, 8286248. [Google Scholar] [CrossRef] [Green Version]
  113. Erbay, E.; Park, I.-H.; Nuzzi, P.D.; Schoenherr, C.J.; Chen, J. IGF-II Transcription in Skeletal Myogenesis Is Controlled by MTOR and Nutrients. J. Cell Biol. 2003, 163, 931–936. [Google Scholar] [CrossRef] [Green Version]
  114. Li, G.; Luo, W.; Abdalla, B.A.; Ouyang, H.; Yu, J.; Hu, F.; Nie, Q.; Zhang, X. MiRNA-223 Upregulated by MYOD Inhibits Myoblast Proliferation by Repressing IGF2 and Facilitates Myoblast Differentiation by Inhibiting ZEB1. Cell Death Dis. 2017, 8, e3094. [Google Scholar] [CrossRef]
  115. Ge, Y.; Sun, Y.; Chen, J. IGF-II Is Regulated by MicroRNA-125b in Skeletal Myogenesis. J. Cell Biol. 2011, 192, 69–81. [Google Scholar] [CrossRef] [Green Version]
  116. Russo, V.C.; Gluckman, P.D.; Feldman, E.L.; Werther, G.A. The Insulin-like Growth Factor System and Its Pleiotropic Functions in Brain. Endocr. Rev. 2005, 26, 916–943. [Google Scholar] [CrossRef] [Green Version]
  117. Cline, B.H.; Steinbusch, H.W.; Malin, D.; Revishchin, A.V.; Pavlova, G.V.; Cespuglio, R.; Strekalova, T. The Neuronal Insulin Sensitizer Dicholine Succinate Reduces Stress-Induced Depressive Traits and Memory Deficit: Possible Role of Insulin-like Growth Factor 2. BMC Neurosci. 2012, 13, 110. [Google Scholar] [CrossRef] [Green Version]
  118. Bannerman, D.M.; Rawlins, J.N.P.; McHugh, S.B.; Deacon, R.M.J.; Yee, B.K.; Bast, T.; Zhang, W.-N.; Pothuizen, H.H.J.; Feldon, J. Regional Dissociations within the Hippocampus—Memory and Anxiety. Neurosci. Biobehav. Rev. 2004, 28, 273–283. [Google Scholar] [CrossRef]
  119. Fromer, M.; Roussos, P.; Sieberts, S.K.; Johnson, J.S.; Kavanagh, D.H.; Perumal, T.M.; Ruderfer, D.M.; Oh, E.C.; Topol, A.; Shah, H.R.; et al. Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia. Nat. Neurosci. 2016, 19, 1442–1453. [Google Scholar] [CrossRef] [Green Version]
  120. Ouchi, Y.; Banno, Y.; Shimizu, Y.; Ando, S.; Hasegawa, H.; Adachi, K.; Iwamoto, T. Reduced Adult Hippocampal Neurogenesis and Working Memory Deficits in the Dgcr8-Deficient Mouse Model of 22q11.2 Deletion-Associated Schizophrenia Can Be Rescued by IGF2. J. Neurosci. 2013, 33, 9408–9419. [Google Scholar] [CrossRef]
  121. Yang, Y.-J.; Luo, T.; Zhao, Y.; Jiang, S.-Z.; Xiong, J.-W.; Zhan, J.-Q.; Yu, B.; Yan, K.; Wei, B. Altered Insulin-like Growth Factor-2 Signaling Is Associated with Psychopathology and Cognitive Deficits in Patients with Schizophrenia. PLoS ONE 2020, 15, e0226688. [Google Scholar] [CrossRef] [Green Version]
  122. Allodi, I.; Comley, L.; Nichterwitz, S.; Nizzardo, M.; Simone, C.; Benitez, J.A.; Cao, M.; Corti, S.; Hedlund, E. Differential Neuronal Vulnerability Identifies IGF-2 as a Protective Factor in ALS. Sci. Rep. 2016, 6, 25960. [Google Scholar] [CrossRef] [Green Version]
  123. García-Huerta, P.; Troncoso-Escudero, P.; Wu, D.; Thiruvalluvan, A.; Cisternas-Olmedo, M.; Henríquez, D.R.; Plate, L.; Chana-Cuevas, P.; Saquel, C.; Thielen, P.; et al. Insulin-like Growth Factor 2 (IGF2) Protects against Huntington’s Disease through the Extracellular Disposal of Protein Aggregates. Acta Neuropathol. 2020, 140, 737–764. [Google Scholar] [CrossRef]
  124. Osborn, T.M.; Beagan, J.; Isacson, O. Increased Motor Neuron Resilience by Small Molecule Compounds That Regulate IGF-II Expression. Neurobiol. Dis. 2018, 110, 218–230. [Google Scholar] [CrossRef]
  125. Steinmetz, A.B.; Stern, S.A.; Kohtz, A.S.; Descalzi, G.; Alberini, C.M. Insulin-Like Growth Factor II Targets the MTOR Pathway to Reverse Autism-Like Phenotypes in Mice. J. Neurosci. 2018, 38, 1015–1029. [Google Scholar] [CrossRef]
  126. Patti, G.; De Mori, L.; Tortora, D.; Severino, M.; Calevo, M.; Russo, S.; Napoli, F.; Confalonieri, L.; Schiavone, M.; Thiabat, H.F.; et al. Cognitive Profiles and Brain Volume Are Affected in Patients with Silver–Russell Syndrome. J. Clin. Endocrinol. Metab. 2020, 105, e1478–e1488. [Google Scholar] [CrossRef]
  127. Azzi, S.; Salem, J.; Thibaud, N.; Chantot-Bastaraud, S.; Lieber, E.; Netchine, I.; Harbison, M.D. A Prospective Study Validating a Clinical Scoring System and Demonstrating Phenotypical-Genotypical Correlations in Silver-Russell Syndrome. J. Med. Genet. 2015, 52, 446–453. [Google Scholar] [CrossRef] [Green Version]
  128. Begemann, M.; Zirn, B.; Santen, G.; Wirthgen, E.; Soellner, L.; Büttel, H.-M.; Schweizer, R.; van Workum, W.; Binder, G.; Eggermann, T. Paternally Inherited IGF2 Mutation and Growth Restriction. N. Engl. J. Med. 2015, 373, 349–356. [Google Scholar] [CrossRef] [Green Version]
  129. Gicquel, C.; Rossignol, S.; Cabrol, S.; Houang, M.; Steunou, V.; Barbu, V.; Danton, F.; Thibaud, N.; Le Merrer, M.; Burglen, L.; et al. Epimutation of the Telomeric Imprinting Center Region on Chromosome 11p15 in Silver-Russell Syndrome. Nat. Genet. 2005, 37, 1003–1007. [Google Scholar] [CrossRef]
  130. Netchine, I.; Rossignol, S.; Dufourg, M.-N.; Azzi, S.; Rousseau, A.; Perin, L.; Houang, M.; Steunou, V.; Esteva, B.; Thibaud, N.; et al. 11p15 Imprinting Center Region 1 Loss of Methylation Is a Common and Specific Cause of Typical Russell-Silver Syndrome: Clinical Scoring System and Epigenetic-Phenotypic Correlations. J. Clin. Endocrinol. Metab. 2007, 92, 3148–3154. [Google Scholar] [CrossRef]
  131. Masunaga, Y.; Inoue, T.; Yamoto, K.; Fujisawa, Y.; Sato, Y.; Kawashima-Sonoyama, Y.; Morisada, N.; Iijima, K.; Ohata, Y.; Namba, N.; et al. IGF2 Mutations. J. Clin. Endocrinol. Metab. 2020, 105, 116–125. [Google Scholar] [CrossRef]
  132. Brioude, F.; Oliver-Petit, I.; Blaise, A.; Praz, F.; Rossignol, S.; Le Jule, M.; Thibaud, N.; Faussat, A.-M.; Tauber, M.; Le Bouc, Y.; et al. CDKN1C Mutation Affecting the PCNA-Binding Domain as a Cause of Familial Russell Silver Syndrome. J. Med. Genet. 2013, 50, 823–830. [Google Scholar] [CrossRef] [PubMed]
  133. Lokulo-Sodipe, O.; Ballard, L.; Child, J.; Inskip, H.M.; Byrne, C.D.; Ishida, M.; Moore, G.E.; Wakeling, E.L.; Fenwick, A.; Mackay, D.J.G.; et al. Phenotype of Genetically Confirmed Silver-Russell Syndrome beyond Childhood. J. Med. Genet. 2020, 57, 683–691. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Van der Steen, M.; Lem, A.J.; van der Kaay, D.C.M.; Bakker-van Waarde, W.M.; van der Hulst, F.J.P.C.M.; Neijens, F.S.; Noordam, C.; Odink, R.J.; Oostdijk, W.; Schroor, E.J.; et al. Metabolic Health in Short Children Born Small for Gestational Age Treated with Growth Hormone and Gonadotropin-Releasing Hormone Analog: Results of a Randomized, Dose-Response Trial. J. Clin. Endocrinol. Metab. 2015, 100, 3725–3734. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Barker, D.J.; Gluckman, P.D.; Godfrey, K.M.; Harding, J.E.; Owens, J.A.; Robinson, J.S. Fetal Nutrition and Cardiovascular Disease in Adult Life. Lancet 1993, 341, 938–941. [Google Scholar] [CrossRef]
  136. Temple, I.K.; Cockwell, A.; Hassold, T.; Pettay, D.; Jacobs, P. Maternal Uniparental Disomy for Chromosome 14. J. Med. Genet. 1991, 28, 511–514. [Google Scholar] [CrossRef] [PubMed]
  137. Kagami, M.; Nagasaki, K.; Kosaki, R.; Horikawa, R.; Naiki, Y.; Saitoh, S.; Tajima, T.; Yorifuji, T.; Numakura, C.; Mizuno, S.; et al. Temple Syndrome: Comprehensive Molecular and Clinical Findings in 32 Japanese Patients. Genet. Med. 2017, 19, 1356–1366. [Google Scholar] [CrossRef] [Green Version]
  138. Scott, J.; Cowell, J.; Robertson, M.E.; Priestley, L.M.; Wadey, R.; Hopkins, B.; Pritchard, J.; Bell, G.I.; Rall, L.B.; Graham, C.F. Insulin-like Growth Factor-II Gene Expression in Wilms’ Tumour and Embryonic Tissues. Nature 1985, 317, 260–262. [Google Scholar] [CrossRef]
  139. Rainier, S.; Johnson, L.A.; Dobry, C.J.; Ping, A.J.; Grundy, P.E.; Feinberg, A.P. Relaxation of Imprinted Genes in Human Cancer. Nature 1993, 362, 747–749. [Google Scholar] [CrossRef]
  140. Ogawa, O.; Eccles, M.R.; Szeto, J.; McNoe, L.A.; Yun, K.; Maw, M.A.; Smith, P.J.; Reeve, A.E. Relaxation of Insulin-like Growth Factor II Gene Imprinting Implicated in Wilms’ Tumour. Nature 1993, 362, 749–751. [Google Scholar] [CrossRef]
  141. Taniguchi, T.; Sullivan, M.J.; Ogawa, O.; Reeve, A.E. Epigenetic Changes Encompassing the IGF2/H19 Locus Associated with Relaxation of IGF2 Imprinting and Silencing of H19 in Wilms Tumor. Proc. Natl. Acad. Sci. USA 1995, 92, 2159–2163. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Brioude, F.; Kalish, J.M.; Mussa, A.; Foster, A.C.; Bliek, J.; Ferrero, G.B.; Boonen, S.E.; Cole, T.; Baker, R.; Bertoletti, M.; et al. Expert Consensus Document: Clinical and Molecular Diagnosis, Screening and Management of Beckwith-Wiedemann Syndrome: An International Consensus Statement. Nat. Rev. Endocrinol. 2018, 14, 229–249. [Google Scholar] [CrossRef] [PubMed]
  143. Maas, S.M.; Vansenne, F.; Kadouch, D.J.M.; Ibrahim, A.; Bliek, J.; Hopman, S.; Mannens, M.M.; Merks, J.H.M.; Maher, E.R.; Hennekam, R.C. Phenotype, Cancer Risk, and Surveillance in Beckwith-Wiedemann Syndrome Depending on Molecular Genetic Subgroups. Am. J. Med. Genet. Part A 2016, 170, 2248–2260. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Horii, T.; Morita, S.; Hino, S.; Kimura, M.; Hino, Y.; Kogo, H.; Nakao, M.; Hatada, I. Successful Generation of Epigenetic Disease Model Mice by Targeted Demethylation of the Epigenome. Genome Biol. 2020, 21, 77. [Google Scholar] [CrossRef]
  145. Giabicani, E.; Pham, A.; Sélénou, C.; Sobrier, M.-L.; Andrique, C.; Lesieur, J.; Linglart, A.; Poliard, A.; Chaussain, C.; Netchine, I. Dental Pulp Stem Cells as a Promising Model to Study Imprinting Diseases. Int. J. Oral Sci. 2022, 14, 19. [Google Scholar] [CrossRef]
Figure 1. Schematic representation of the modes of action of IGF-II. In the bloodstream, IGF-II is mostly bound in a ternary complex with the acid-labile subunit (ALS) and IGF-binding proteins (IGFBP)-3 and -5. Once released from this complex by PAPP-A2 proteolysis, IGF-II can bind either the type A insulin receptor (INSR-A) or IGF receptor type 1 or 2 (IGF-1R and IGF-2R), inducing cell proliferation or IGF-II clearance.
Figure 1. Schematic representation of the modes of action of IGF-II. In the bloodstream, IGF-II is mostly bound in a ternary complex with the acid-labile subunit (ALS) and IGF-binding proteins (IGFBP)-3 and -5. Once released from this complex by PAPP-A2 proteolysis, IGF-II can bind either the type A insulin receptor (INSR-A) or IGF receptor type 1 or 2 (IGF-1R and IGF-2R), inducing cell proliferation or IGF-II clearance.
Cells 11 01886 g001
Figure 2. The human IGF2/H19 11p15.5 locus. (A) The IGF2 and H19 genes are separated by about 80 kb. IGF2 is paternally expressed (blue arrow), whereas H19 is maternally expressed (red arrow). The four DMR (green boxes) and enhancers (yellow ellipses) are represented. (B) H19/IGF2:IG-DMR (ICR1) in detail: OCT4/SOX2 (blue stars) and CTCF (green circles) binding sites on the maternal allele (red), and methylation sites (black lollipops), ZFP57 binding sites (orange stars) and the undefined ZNF445 binding site consensus sequence (purple dash) on the paternal allele (blue) are shown.
Figure 2. The human IGF2/H19 11p15.5 locus. (A) The IGF2 and H19 genes are separated by about 80 kb. IGF2 is paternally expressed (blue arrow), whereas H19 is maternally expressed (red arrow). The four DMR (green boxes) and enhancers (yellow ellipses) are represented. (B) H19/IGF2:IG-DMR (ICR1) in detail: OCT4/SOX2 (blue stars) and CTCF (green circles) binding sites on the maternal allele (red), and methylation sites (black lollipops), ZFP57 binding sites (orange stars) and the undefined ZNF445 binding site consensus sequence (purple dash) on the paternal allele (blue) are shown.
Cells 11 01886 g002
Figure 3. (A) Schematic representation of the structure of the IGF2 gene in humans. The IGF2 gene consists of 10 exons and is driven by five different promotors. The exons of the IGF2 gene are boxed. The black boxes indicate non-coding exons. The colored boxes indicate the coding exons. The turned arrows show the promotors (P) and indicate the transcription start sites. The blue lines indicate the differentially methylated regions (DMR) in the IGF2 gene. (B) Transcripts of the human IGF2 gene. IGF2 has six alternative transcripts, depending on promotors and splice sites used. (C) Human IGF-II proteins. IGF-II has two precursor proteins. Only exons 5, 8, 9 and 10 encode IGF-II proteins. Exon 5 is not included in the composition of the second precursor protein, which therefore has a smaller signal peptide. SP: signal peptide; AA: amino acids.
Figure 3. (A) Schematic representation of the structure of the IGF2 gene in humans. The IGF2 gene consists of 10 exons and is driven by five different promotors. The exons of the IGF2 gene are boxed. The black boxes indicate non-coding exons. The colored boxes indicate the coding exons. The turned arrows show the promotors (P) and indicate the transcription start sites. The blue lines indicate the differentially methylated regions (DMR) in the IGF2 gene. (B) Transcripts of the human IGF2 gene. IGF2 has six alternative transcripts, depending on promotors and splice sites used. (C) Human IGF-II proteins. IGF-II has two precursor proteins. Only exons 5, 8, 9 and 10 encode IGF-II proteins. Exon 5 is not included in the composition of the second precursor protein, which therefore has a smaller signal peptide. SP: signal peptide; AA: amino acids.
Cells 11 01886 g003
Figure 4. Adapted from Rovina et al. [60]. Three-dimensional representation of the IGF2-H19 locus on the paternal (left) and maternal (right) chromosomes. The ICR1 of the paternal allele is methylated (black lollipops), with enhancers A and B (yellow ellipses) close to the IGF2 promoter; this conformation allows IGF2 expression and H19 repression. The CTCF of the maternal allele can bind the unmethylated ICR1 (green circles), regulating the interaction with DMR1 (green box) and the matrix attachment region (MAR)3 (brown box); the A and B (yellow ellipses) enhancers are close to the H19 promoter. This conformation allows H19 expression and IGF2 repression.
Figure 4. Adapted from Rovina et al. [60]. Three-dimensional representation of the IGF2-H19 locus on the paternal (left) and maternal (right) chromosomes. The ICR1 of the paternal allele is methylated (black lollipops), with enhancers A and B (yellow ellipses) close to the IGF2 promoter; this conformation allows IGF2 expression and H19 repression. The CTCF of the maternal allele can bind the unmethylated ICR1 (green circles), regulating the interaction with DMR1 (green box) and the matrix attachment region (MAR)3 (brown box); the A and B (yellow ellipses) enhancers are close to the H19 promoter. This conformation allows H19 expression and IGF2 repression.
Cells 11 01886 g004
Figure 5. Diagram summarizing the physiological roles of IGF-II described in humans and mouse models.
Figure 5. Diagram summarizing the physiological roles of IGF-II described in humans and mouse models.
Cells 11 01886 g005
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Sélénou, C.; Brioude, F.; Giabicani, E.; Sobrier, M.-L.; Netchine, I. IGF2: Development, Genetic and Epigenetic Abnormalities. Cells 2022, 11, 1886. https://doi.org/10.3390/cells11121886

AMA Style

Sélénou C, Brioude F, Giabicani E, Sobrier M-L, Netchine I. IGF2: Development, Genetic and Epigenetic Abnormalities. Cells. 2022; 11(12):1886. https://doi.org/10.3390/cells11121886

Chicago/Turabian Style

Sélénou, Céline, Frédéric Brioude, Eloïse Giabicani, Marie-Laure Sobrier, and Irène Netchine. 2022. "IGF2: Development, Genetic and Epigenetic Abnormalities" Cells 11, no. 12: 1886. https://doi.org/10.3390/cells11121886

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop