Chapter Ten - Ultradian Oscillations in Notch Signaling Regulate Dynamic Biological Events
Introduction
Upon activation of Notch signaling, the Notch intracellular domain (NICD) is released from the membrane region and is transferred to the nucleus, where NICD forms a complex with the DNA-binding protein RBPj (Fig. 10.1A) (Honjo, 1996, Kopan and Ilagan, 2009). The NICD–RBPj complex recruits additional transcriptional activators and induces downstream genes such as Hes and Hey genes, forming the Notch–RBPj–Hes axis, often called the canonical pathway (Fig. 10.1A). Hes genes are mammalian homologues of Drosophila hairy and Enhancer of split and encode basic helix-loop-helix (bHLH)-type transcriptional repressors (Fig. 10.1B) (Sasai et al., 1992, Kageyama et al., 2007). There are seven members in the Hes family (Hes1 to Hes7), although Hes4 is not present in the mouse genome. Through their bHLH domain, Hes factors form homodimers or heterodimers with Hes-related bHLH factors such as Hey1 and bind to the DNA sequences called the N box (CACNAG) or the class C site (CACG(C/A)G) (Iso et al., 2003, Kageyama et al., 2007). In addition, Hes factors contain an orange domain located just C-terminal to the bHLH domain followed by the WRPW sequence at the carboxyl terminus, and both the orange domain and the WRPW sequence recruit several co-repressors. Thus, Hes proteins act as transcriptional repressors by binding to the target sequences. The orange domain also regulates the selection of bHLH heterodimer partners (Dawson et al., 1995, Taelman et al., 2004), while the WRPW sequence acts as a polyubiquitination signal, controlling the half-life of Hes protein by promotion of proteasome-mediated degradation (Kang et al., 2005).
It is well established that the Notch–RBPj–Hes pathway regulates many biological events by repressing target gene expression (Honjo, 1996, Kageyama et al., 2007. Major Hes target genes include proneural genes such as Mash1 and Neurogenin2 (Ngn2), themselves bHLH proteins acting as transcriptional activators (Fig. 10.1A) (Bertrand et al., 2002, Ross et al., 2003). Proneural genes promote differentiation of neural stem cells into neurons, while Hes genes repress proneural gene expression and maintain neural stem cells (Kageyama et al., 2007). Other major Hes target genes are Hes genes themselves (Fig. 10.1A) (Takebayashi et al., 1994, Bessho et al., 2003). For example, Hes1 and Hes7 can repress their own expression by directly binding to their own promoters, thereby forming negative feedback loops. This negative feedback is sufficient to produce oscillating gene expression (Hirata et al., 2002, Bessho et al., 2003). In this chapter, we describe the mechanism and significance of oscillating Hes expression in somite formation, neural development, and embryonic stem (ES) cell differentiation and discuss that not only the expression level but also the expression mode (oscillating versus sustained) is very important for many biological events.
Section snippets
Hes7 oscillations by negative feedback
Somites are segmental axial structures of vertebrate embryos that give rise to vertebral column, ribs, skeletal muscles, and subcutaneous tissues. A bilateral pair of somites forms periodically at the anterior ends of the presomitic mesoderm (PSM), located at the caudal part of embryos (Fig. 10.2A). During this process, mesenchymal cells of the PSM are transformed into the epithelial sheet (mesenchymal–epithelial transition) at each somite border, which segments a block of somitic cells from
The role of bHLH genes in neural development
In the developing nervous system, neuroepithelial cells proliferate extensively by repeated replicative, or symmetric, cell division. In such division, each dividing neuroepithelial cell will produce two neuroepithelial cells (Fig. 10.6). As neural development proceeds, neuroepithelial cells become gradually elongated and adopt the fate of radial glial cells. Each radial glial cell has its cell body in an inner layer lining the ventricle, thus called the ventricular zone; each cell extends a
Hes1 Oscillations Regulate ES Cell Differentiation
ES cells have the ability to differentiate into cell types of all three germ layers (pluripotency), and application of these cells to regenerative medicine is greatly anticipated. However, ES cells are heterogeneous in response to differentiation cues, and it is very difficult to direct their differentiation into a pure population of desired cell types. The molecular mechanism of such heterogeneity of ES cells in differentiation responses is not well understood. Recent studies have shown that
Conclusions
The above results suggest that oscillatory expression with short periods (ultradian oscillation) is important for many biological events. During somite segmentation, oscillations occur in a synchronized manner between neighboring cells in the PSM, and each cycle leads to segmentation of a bilateral pair of somites. In this case, oscillators function as a biological clock. However, unlike the circadian clock, the oscillation period of the segmentation clock is species specific and temperature
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Notch signaling in the division of germ layers in bilaterian embryos
2018, Mechanisms of DevelopmentCitation Excerpt :Therefore, Hes1 oscillation contributes to the heterogeneity of cell fate choices in mESc. When differentiation signals appear, high, sustained Hes1 expression promotes mesodermal progenitor fates and inhibits neural fates by directly repressing Notch ligands, whereas at low Hes1 levels, mESc tend to adopt the neural fate (Kageyama et al., 2010). Canonical Wnt/nβ-cat signaling is absolutely required in vivo in the epiblast for primitive streak and mesoderm formation, since they are absent from knock-out mice embryos of β-cat or Wnt3 (Huelsken et al., 2000; Liu et al., 1999).
Hes3 is expressed in the adult pancreatic islet and regulates gene expression, cell growth, and insulin release
2014, Journal of Biological ChemistryCitation Excerpt :This could be especially important because, as we show, both forms are present in total pancreas tissue and the levels of the transcripts appear to be differentially regulated during postnatal development. In light of recent work showing that oscillatory versus sustained expression of Hes/Hey and other related genes contributes to cell fate specification (7), it will be useful to address, in future studies, the regulation of the expression of each Hes3 form. The repressor activity of Hes3 renders it a difficult gene to study, being a candidate for transcriptional squelching.
Limb patterning: From signaling gradients to molecular oscillations
2014, Journal of Molecular BiologyExpression dynamics and functions of hes factors in development and diseases
2014, Current Topics in Developmental BiologyCitation Excerpt :It is also important to address the detailed molecular mechanisms maintaining Hes1 oscillation with biochemical studies and those that switch the expression modes between oscillatory and sustained expressions. Oscillations were also reported in some signaling pathways regulating Hes factors, such as Notch, Jak–Stat, and Fgf signalings (Kageyama, Niwa, Shimojo, Kobayashi, & Ohtsuka, 2010; Niwa et al., 2007; Yoshiura et al., 2007). For example, Notch and Fgf signaling cooperatively regulate Hes7 oscillation and achieve a spatiotemporal regulation during somite segmentation events (Niwa et al., 2011).