Notch Is a Critical Component of the Mouse Somitogenesis Oscillator and Is Essential for the Formation of the Somites

Abstract

Segmentation of the vertebrate body axis is initiated through somitogenesis, whereby epithelial somites bud off in pairs periodically from the rostral end of the unsegmented presomitic mesoderm (PSM). The periodicity of somitogenesis is governed by a molecular oscillator that drives periodic waves of clock gene expression caudo-rostrally through the PSM with a periodicity that matches somite formation. To date the clock genes comprise components of the Notch, Wnt, and FGF pathways. The literature contains controversial reports as to the absolute role(s) of Notch signalling during the process of somite formation. Recent data in the zebrafish have suggested that the only role of Notch signalling is to synchronise clock gene oscillations across the PSM and that somite formation can continue in the absence of Notch activity. However, it is not clear in the mouse if an FGF/Wnt-based oscillator is sufficient to generate segmented structures, such as the somites, in the absence of all Notch activity. We have investigated the requirement for Notch signalling in the mouse somitogenesis clock by analysing embryos carrying a mutation in different components of the Notch pathway, such as Lunatic fringe (Lfng), Hes7, Rbpj, and presenilin1/presenilin2 (Psen1/Psen2), and by pharmacological blocking of the Notch pathway. In contrast to the fish studies, we show that mouse embryos lacking all Notch activity do not show oscillatory activity, as evidenced by the absence of waves of clock gene expression across the PSM, and they do not develop somites. We propose that, at least in the mouse embryo, Notch activity is absolutely essential for the formation of a segmented body axis.

Anabolic actions of Notch on mature bone

“…Mutations of JAG1 and NOTCH2 in concert cause Alagille syndrome, marked by impaired craniofacial development due to somite segmentation defects. However, mice lacking individual Notch receptors are invariably lethal in utero, likely due to an early deficiency in somite segmentation (7,(9)(10)(11)(41)(42)(43)(44)(45)(46)(47). Nonetheless, double-mutant mice, wherein Prx1-Cre-mediated deletion of Psen1 is restricted to the mesenchyme on a Psen2 −/− background, survive for up to 10 wk and display radiodense bones (13).…”

Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear

“…3A) and targets (Fig. 3B) after incubation with the γ-secretase inhibitor LY411575 (Ferjentsik et al, 2009). As expected from the different regulatory circuits (Notch inhibition or activation of the ligand), Notch blockade showed opposite effects on Dl1 and Jag1 (Fig.…”

Multidimensional quantitative analysis of mRNA expression within intact vertebrate embryos

“…In all vertebrates, somites provide one of the first outward appearances of the metameric body plan, periodically pinching off from the presomitic mesoderm (PSM) in bilaterally symmetrical pairs as precursors to the axial muscles and vertebral column (Oates et al, 2012). To date, detailed studies of the gene dynamics underlying somitogenesis have relied heavily on examination of one-channel (Henry et al, 2002;Oates and Ho, 2002;Mara et al, 2007;Gomez et al, 2008;Ferjentsik et al, 2009;Choorapoikayil et al, 2012;Schroter et al, 2012) and two-channel (Holley et al, 2000;Oates and Ho, 2002;Jülich et al, 2005) CARD images that display expression of one or two mRNAs per embryo. Here, using in situ HCR, we demonstrate quantitative subcellular analyses of four mRNAs in the same embryo.…”