The many roles of Notch signaling during vertebrate somitogenesis

Wahi, Kanu; Bochter, Matthew S.; Cole, Susan E.

doi:10.1016/j.semcdb.2014.11.010

Cited by 42 publications

(35 citation statements)

References 107 publications

(144 reference statements)

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“…Vertebral development requires the precise integration of several signalling cascades, including Notch, FGFs, Shh, Wnt and Bmps (Murtaugh et al, 1999;Maroto et al, 2012;Hubaud and Pourquie, 2014;Wahi et al, 2016). Here, we determine the role of Fat4 and Dchs1 signalling during vertebral development and whether these effects are mediated through alterations in the Hippo pathway or PCP.…”

Section: Fat4mentioning

confidence: 99%

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

et al. 2016

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The protocadherins Fat4 and Dchs1 act as a receptor-ligand pair to regulate many developmental processes in mice and humans, including development of the vertebrae. Based on conservation of function between Drosophila and mammals, Fat4-Dchs1 signalling has been proposed to regulate planar cell polarity (PCP) and activity of the Hippo effectors Yap and Taz, which regulate cell proliferation, survival and differentiation. There is strong evidence for Fat regulation of PCP in mammals but the link with the Hippo pathway is unclear. In Fat4 −/− and Dchs1 −/− mice, many vertebrae are split along the midline and fused across the anterior-posterior axis, suggesting that these defects might arise due to altered cell polarity and/or changes in cell proliferation/differentiation. We show that the somite and sclerotome are specified appropriately, the transcriptional network that drives early chondrogenesis is intact, and that cell polarity within the sclerotome is unperturbed. We find that the key defect in Fat4 and Dchs1 mutant mice is decreased proliferation in the early sclerotome. This results in fewer chondrogenic cells within the developing vertebral body, which fail to condense appropriately along the midline. Analysis of Fat4;Yap and Fat4;Taz double mutants, and expression of their transcriptional target Ctgf, indicates that Fat4-Dchs1 regulates vertebral development independently of Yap and Taz. Thus, we have identified a new pathway crucial for the development of the vertebrae and our data indicate that novel mechanisms of Fat4-Dchs1 signalling have evolved to control cell proliferation within the developing vertebrae.

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Section: Fat4mentioning

confidence: 99%

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

et al. 2016

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“…The rate of somite formation and the specific oscillatory genes essential for somite formation vary widely among vertebrates (Wahi et al, 2016). Mutations in clock genes can result in congenital vertebral defects such as spondylocostal dysostoses, scoliosis, or spinal kyphosis (Turnpenny et al, 2007, Eckalbar et al, 2012), highlighting the importance of normal clock function.…”

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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“…Importantly, as Delta-1 is a direct target of Tbx6 (White and Chapman, 2005), expansion of the Tbx6 expression domain or protein levels could manipulate the speed of the clock. The current model in the field holds that there is very tight coordination between the clock and wavefront position (reviewed by Wahi et al, 2016). Our data suggest that loss of RAR signaling might uncouple this connection.…”

Section: Rarβ2 Loss Of Function Reduces Somite Number and Increases Smentioning

confidence: 60%

RARβ2 is required for vertebrate somitogenesis

et al. 2017

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During vertebrate somitogenesis, retinoic acid is known to establish the position of the determination wavefront, controlling where new somites are permitted to form along the anteroposterior body axis. Less is understood about how RAR regulates somite patterning, rostral-caudal boundary setting, specialization of myotome subdivisions or the specific RAR subtype that is required for somite patterning. Characterizing the function of RARβ has been challenging due to the absence of embryonic phenotypes in murine loss-offunction studies. Using the Xenopus system, we show that RARβ2 plays a specific role in somite number and size, restriction of the presomitic mesoderm anterior border, somite chevron morphology and hypaxial myoblast migration. Rarβ2 is the RAR subtype whose expression is most upregulated in response to ligand and its localization in the trunk somites positions it at the right time and place to respond to embryonic retinoid levels during somitogenesis. RARβ2 positively regulates Tbx3 a marker of hypaxial muscle, and negatively regulates Tbx6 via Ripply2 to restrict the anterior boundaries of the presomitic mesoderm and caudal progenitor pool. These results demonstrate for the first time an early and essential role for RARβ2 in vertebrate somitogenesis.

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The many roles of Notch signaling during vertebrate somitogenesis

Cited by 42 publications

References 107 publications

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

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

RARβ2 is required for vertebrate somitogenesis

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