ReviewPosition- and polarity-dependent Hippo signaling regulates cell fates in preimplantation mouse embryos
Introduction
Mouse embryogenesis occurs under powerful regulatory control. Embryos of other oviparous vertebrates such as zebrafish and Xenopus also employ regulatory mechanisms during embryogenesis, but axis formation depends on maternal determinants localized in unfertilized eggs and zygotes (see reviews [1], [2], [3], [4], [5]). In contrast, the development of mouse embryos does not critically depend on such factors. For example, manipulations such as removal of portions of the zygote or destruction of a single blastomere in embryos at the 8-cell stage do not affect mouse embryonic development. Furthermore, isolated blastomeres at the 4- or 8-cell stage embryos show totipotency when aggregated with host embryos [6], [7], [8], [9], [10], [11].
The ability of mouse embryos to develop properly without using localized information has been a hotly debated topic in developmental biology. Preimplantation mouse development has been under intense scientific scrutiny for many years and several models have been proposed. Recent molecular biology-based insights have revealed Hippo signaling as one of the earliest mechanisms influencing cell fate specification. In this review, I will summarize the role and regulation of the Hippo signaling pathway during the first cell-fate specification of mouse embryo development and discuss their relationships with the historical models.
Section snippets
Preimplantation mouse development
During preimplantation development, mouse embryos form a cyst-like structure called a blastocyst by 3.5 days post-coitus (dpc) (Fig. 1A). The early blastocysts consist of two cell types. The outer epithelial cells constitute the trophectoderm (TE) that is required for implantation into the uterus. At later developmental stages, the TE forms extraembryonic tissues, including the embryonic part of the placenta. The inner cells attached to one end of the TE form the inner cell mass (ICM). The ICM
Hippo signaling pathway
Recently, the Hippo signaling pathway was shown to play an important role in regulating cell fates during embryonic development. The Hippo signaling pathway was originally identified as a tumor suppressor-signaling pathway in Drosophila, but it is also conserved in mice and humans (see reviews [47], [48]). The core components of this signaling pathway (Drosophila counterparts are indicated in parentheses) are the protein kinases Mst1/2 (Hippo) and Lats1/2 (Warts), their respective cofactors
A combination of cell–cell adhesion and cell polarization establishes position-dependent Hippo signaling at the 32-cell stage
Establishment of position-dependent Hippo signaling involves differences in cell polarization: the outer and inner cells are polar and apolar, respectively. Polarization is required for TE development because disruptions of the Par–aPKC system, a key regulator of apicobasal cell polarity [65], prompt cells to take the inner position in mosaic embryos, although TE-specific gene expression has not been examined [66]. Furthermore, disruption of the Par–aPKC system in the entire embryo after
Asymmetric cell division initiates differential Hippo signaling during the 8-to-16-cell stage transition
Although the inner cells are first formed at the 16-cell stage, the mechanisms that establish position-dependent Hippo signaling have been mainly studied at around the 32-cell stage. However, slightly different mechanisms appear to regulate Hippo signaling at the 16- and 32-cell stages. During the 8-to-16-cell transition, some of the blastomeres undergo asymmetric cell division forming one polar and one apolar daughter cell [16], and some of the apolar cells transiently take the outer position
Notch signaling cooperates with Hippo signaling to regulate Cdx2 expression
Recently, Manzanares's group demonstrated the involvement of Notch signaling in regulating Cdx2 expression levels [57]. Analysis of cis-regulatory elements of the Cdx2 gene identified a TE-specific enhancer that reproduced the expression pattern of endogenous Cdx2. The enhancer contains two binding sites for Tead and four binding sites for RBPJ, a transcription factor that functions downstream of the Notch-signaling pathway [57]. Experiments with transgenic Notch-reporter embryos showed that
Roles of Hippo signaling in cell-fate specification during preimplantation development
As reviewed above, Hippo signaling is critically important for cell-fate specification of the ICM in preimplantation mouse embryos. The roles of Hippo signaling may differ depending on the developmental stage. Cooperation of the Hippo-signaling pathway with other regulatory mechanisms in controlling cell fate is summarized by the model depicted in Fig. 4. At the 4-cell stage, blastomeres already differ in terms of their developmental potential, epigenetic modifications, and nuclear retention of
Conclusions
Studies on the Hippo-signaling pathway have revealed that cells integrate information regarding cell–cell adhesion and cell polarization to interpret cell positions. Using this mechanism, embryos can properly establish two cell lineages and form blastocysts. However, several unresolved questions remain. First, the mechanism by which the Par–aPKC system restricts Amot expression is unknown. Second, Hippo signaling is not the only mechanism that controls cell fates, and its relationships with
Acknowledgements
This work was supported by Grants-in-Aid for Scientific Research (KAKENHI) from MEXT (21116003, 26112715, 15H01495) and JSPS (23247036) to H.S.
References (90)
- et al.
A cell surface glycoprotein involved in the compaction of embryonal carcinoma cells and cleavage stage embryos
Cell
(1980) - et al.
The calcium-dependent cell–cell adhesion system regulates inner cell mass formation and cell surface polarization in early mouse development
Cell
(1983) - et al.
The foundation of two distinct cell lineages within the mouse morula
Cell
(1981) - et al.
Origin of the inner cell mass in mouse embryos: cell lineage analysis by microinjection
Dev Biol
(1986) A quantitative analysis of cell allocation to trophectoderm and inner cell mass in the mouse blastocyst
Dev Biol
(1987)- et al.
Lineage mapping the pre-implantation mouse embryo by two-photon microscopy, new insights into the segregation of cell fates
Dev Biol
(2011) - et al.
Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4
Cell
(1998) - et al.
Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells
Cell
(2003) - et al.
The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells
Cell
(2003) - et al.
Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst
Dev Cell
(2010)
Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extra embryonic cell lineages involved in implantation
Dev Biol
Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation
Cell
A role for Id2 in regulating photic entrainment of the mammalian circadian system
Curr Biol
Blastomeres of the mouse embryo lose totipotency after the fifth cleavage division: expression of Cdx2 and Oct4 and developmental potential of inner and outer blastomeres of 16- and 32-cell embryos
Dev Biol
Relative contribution of cell contact pattern, specific PKC isoforms and gap junctional communication in tight junction assembly in the mouse early embryo
Dev Biol
The roles of phenotype and position in guiding the fate of 16-cell mouse blastomeres
Dev Biol
Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos
Mech Dev
Notch and hippo converge on Cdx2 to specify the trophectoderm lineage in the mouse blastocyst
Dev Cell
The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass
Dev Cell
The Hippo pathway member Nf2 is required for inner cell mass specification
Curr Biol
Polarity-dependent distribution of angiomotin localizes hippo signaling in preimplantation embryos
Curr Biol
Potential of isolated mouse inner cell masses to form trophectoderm derivatives in vivo
Dev Biol
Angiomotin-like proteins associate with and negatively regulate YAP1
J Biol Chem
Hippo pathway-independent restriction of TAZ and YAP by angiomotin
J Biol Chem
A tight junction-associated Merlin-angiomotin complex mediates Merlin's regulation of mitogenic signaling and tumor suppressive functions
Cancer Cell
The NF2 tumor suppressor, merlin, regulates epidermal development through the establishment of a junctional polarity complex
Dev Cell
Differential roles of p80- and p130-angiomotin in the switch between migration and stabilization of endothelial cells
Biochim Biophys Acta
Phosphorylation of angiomotin by Lats1/2 kinases inhibits F-actin binding, cell migration and angiogenesis
J Biol Chem
Actin-binding and cell proliferation activities of angiomotin family members are regulated by Hippo pathway-mediated phosphorylation
J Biol Chem
A Rich1/Amot complex regulates the Cdc42 GTPase and apical-polarity proteins in epithelial cells
Cell
Developmental bias in cleavage-stage mouse blastomeres
Curr Biol
Lgl regulates Notch signaling via endocytosis, independently of the apical aPKC-Par6-Baz polarity complex
Curr Biol
The Hippo superhighway: signaling crossroads converging on the Hippo/Yap pathway in stem cells and development
Curr Opin Cell Biol
The establishment of Spemann's organizer and patterning of the vertebrate embryo
Nat Rev
Spemann's organizer and self-regulation in amphibian embryos
Nat Rev Mol Cell Biol
Cortical rotation of the Xenopus egg: consequences for the anteroposterior pattern of embryonic dorsal development
Development
Organizer formation and function
Results Probl Cell Differ
Molecular genetics of axis formation in zebrafish
Annu Rev Genet
Studies of the developmental potential of 4- and 8-cell stage mouse blastomeres
J Exp Zool
Postimplantation development of blastomeres isolated from 4- and 8-cell mouse eggs
J Embryol Exp Morphol
Experiments on the development of isolated blastomers of mouse eggs
Nature
Experimental studies on regulation in the development of isolated blastomeres of mouse embryos
Acta Theriol III
Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage
J Embryol Exp Morphol
Fertile offspring derived from mammalian eggs lacking either animal or vegetal poles
Development
E-cadherin null mutant embryos fail to form a trophectoderm epithelium
Proc Natl Acad Sci U S A
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