Delta-Notch signalling in segmentation

Liao, Bokai; Oates, Andrew C.

doi:10.1016/j.asd.2016.11.007

Cited by 59 publications

(53 citation statements)

References 233 publications

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“…In all vertebrates examined to date, at least one Notch pathway component or target exhibits cyclic expression, linking Notch activation to clock function (Liao and Oates, 2016). However, the specific Notch pathway components that oscillate in the clock vary among species.…”

Section: Introductionmentioning

confidence: 99%

Putative binding sites for mir‐125 family miRNAs in the mouse Lfng 3′UTR affect transcript expression in the segmentation clock, but mir‐125a‐5p is dispensable for normal somitogenesis

Wahi

Friesen

Coppola

et al. 2017

Developmental Dynamics

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Background In vertebrate embryos, a "segmentation clock" times somitogenesis. Clock-linked genes, including Lunatic fringe (Lfng), exhibit cyclic expression in the presomitic mesoderm (PSM), with a period matching the rate of somite formation. The clock period varies widely across species, but the mechanisms that underlie this variability are not clear. The half-lives of clock components are proposed to influence the rate of clock oscillations, and are tightly regulated in the PSM. Interactions between Lfng and mir-125a-5p in the embryonic chicken PSM promote Lfng transcript instability, but the conservation of this mechanism in other vertebrates has not been tested. Here, we examine whether this interaction affects clock activity in a mammalian species. Results Mutation of mir-125 binding sites in the Lfng 3'UTR leads to persistent, non-oscillatory reporter transcript expression in the caudal-most mouse PSM, though dynamic transcript expression recovers in the central PSM. Despite this, expression of endogenous mir-125a-5p is dispensable for mouse somitogenesis. Conclusions These results suggest that mir-125a sites in the Lfng 3'UTR influence transcript turnover in both mouse and chicken embryos, and support the existence of position-dependent regulatory mechanisms in the PSM. They further suggest the existence of compensatory mechanisms that can rescue the loss of mir-125a-5p in mice.

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Section: Introductionmentioning

confidence: 99%

Putative binding sites for mir‐125 family miRNAs in the mouse Lfng 3′UTR affect transcript expression in the segmentation clock, but mir‐125a‐5p is dispensable for normal somitogenesis

Wahi

Friesen

Coppola

et al. 2017

Developmental Dynamics

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show abstract

“…As the most highly conserved pathway involved in the segmentation clock, a wealth of studies have focused on elucidating the fundamental role of Notch in somitogenesis and in the segmentation clock mechanism (Barrantes et al, 1999; Jiang et al, 2000; Bessho et al, 2001b, 2003; Dale et al, 2003; Julich et al, 2005; McGrew et al, 2008; Hubaud and Pourquie, 2014; Wahi et al, 2014; Liao and Oates, 2016). Notch is clearly required to synchronize oscillations between neighboring cells (Jiang et al, 2000; Shimojo et al, 2016).…”

Section: Somitogenesismentioning

confidence: 99%

“…A question that arises is whether oscillations are actually necessary for the segmentation process to occur or whether just non-oscillatory activity of the Notch pathway is sufficient. Mutant mice or fish lacking Notch components all display severe segmentation defects (Conlon et al, 1995; Barrantes et al, 1999; Jiang et al, 2000; Liao and Oates, 2016). For example, the lack of the obligate transcription factor RBP-J κ, in mouse, leads to lethality before day E10.5 and only the first few cervical somites are formed (Oka et al, 1995).…”

Section: Somitogenesismentioning

confidence: 99%

Turn It Down a Notch

Carrieri

Dale

2017

Front. Cell Dev. Biol.

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In the developing vertebrate embryo, segmentation initiates through the formation of repeated segments, or somites, on either side of the posterior neural tube along the anterior to posterior axis. The periodicity of somitogenesis is regulated by a molecular oscillator, the segmentation clock, driving cyclic gene expression in the unsegmented paraxial mesoderm, from which somites derive. Three signaling pathways underlie the molecular mechanism of the oscillator: Wnt, FGF, and Notch. In particular, Notch has been demonstrated to be an essential piece in the intricate somitogenesis regulation puzzle. Notch is required to synchronize oscillations between neighboring cells, and is moreover necessary for somite formation and clock gene oscillations. Following ligand activation, the Notch receptor is cleaved to liberate the active intracellular domain (NICD) and during somitogenesis NICD itself is produced and degraded in a cyclical manner, requiring tightly regulated, and coordinated turnover. It was recently shown that the pace of the segmentation clock is exquisitely sensitive to levels/stability of NICD. In this review, we focus on what is known about the mechanisms regulating NICD turnover, crucial to the activity of the pathway in all developmental contexts. To date, the regulation of NICD stability has been attributed to phosphorylation of the PEST domain which serves to recruit the SCF/Sel10/FBXW7 E3 ubiquitin ligase complex involved in NICD turnover. We will describe the pathophysiological relevance of NICD-FBXW7 interaction, whose defects have been linked to leukemia and a variety of solid cancers.

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“…Synchronization of clock gene oscillations between neighbouring cells is reliant on Notch signalling [10][11][12][13]. Synchronization of clock gene oscillations between neighbouring cells is reliant on Notch signalling [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

CDK 1 and CDK 2 regulate NICD 1 turnover and the periodicity of the segmentation clock

et al. 2019

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All vertebrates share a segmented body axis. Segments form from the rostral end of the presomitic mesoderm (PSM) with a periodicity that is regulated by the segmentation clock. The segmentation clock is a molecular oscillator that exhibits dynamic clock gene expression across the PSM with a periodicity that matches somite formation. Notch signalling is crucial to this process. Altering Notch intracellular domain (NICD) stability affects both the clock period and somite size. However, the mechanism by which NICD stability is regulated in this context is unclear. We identified a highly conserved site crucial for NICD recognition by the SCF E3 ligase, which targets NICD for degradation. We demonstrate both CDK1 and CDK2 can phosphorylate NICD in the domain where this crucial residue lies and that NICD levels vary in a cell cycle‐dependent manner. Inhibiting CDK1 or CDK2 activity increases NICD levels both in vitro and in vivo, leading to a delay of clock gene oscillations and an increase in somite size.

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Delta-Notch signalling in segmentation

Cited by 59 publications

References 233 publications

Putative binding sites for mir‐125 family miRNAs in the mouse Lfng 3′UTR affect transcript expression in the segmentation clock, but mir‐125a‐5p is dispensable for normal somitogenesis

Putative binding sites for mir‐125 family miRNAs in the mouse Lfng 3′UTR affect transcript expression in the segmentation clock, but mir‐125a‐5p is dispensable for normal somitogenesis

Turn It Down a Notch

CDK 1 and CDK 2 regulate NICD 1 turnover and the periodicity of the segmentation clock

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