Notch signaling, the segmentation clock, and the patterning of vertebrate somites

Abstract

N No ot tc ch h s si ig gn na al li in ng g, , t th he e s se eg gm me en nt ta at ti io on n c cl lo oc ck k, , a an nd d t th he e p pa at tt te er rn ni in ng g o of f v ve er rt te eb br ra at te e s so om mi it te es s In one way or another, at one stage or another, almost every tissue in an animal body depends for its patterning on the Notch cell-cell signaling pathway [1]. The evidence from mutants is clear: disrupted Notch signaling entails disrupted pattern. The challenge is to define precisely what it is that Notch signaling does in any given case, and when it does it. This problem is posed in a particularly striking and curious way by the phenomena of somitogenesis -the process by which the vertebrate embryo lays down the regular sequence of tissue blocks that will give rise to the musculoskeletal segments of the neck, trunk, and tail.These blocks of embryonic tissue, the somites, are arranged symmetrically in a neat, repetitive pattern on either side of the central body axis. Each somite is separated from the next by a cleft -the segment boundary; and each somite has a definite polarity, with an anterior portion and posterior portion expressing different sets of genes [2]. Mutations in components of the Notch signaling pathway play havoc with this whole pattern: although somites may eventually form, the segment boundaries are irregular and randomly positioned, and the regular antero-posterior polarity of individual somites is lost. Genetic screens for mutations that disrupt segmentation in this way chiefly identify Notch pathway components as the critical players. Notch signaling is clearly central to somitogenesis [3][4][5][6]. But precisely how? N No ot tc ch h p pa at th hw wa ay y c co om mp po on ne en nt ts s c ca an n b be e w wi ir re ed d t to og ge et th he er r i in n d di if ff fe er re en nt t w wa ay ys s f fo or r d di if ff fe er re en nt t o ou ut tc co om me es sIn general, the function of the canonical Notch pathway is to coordinate gene expression in contiguous cells. It does this in a particularly direct way. The signal-sending cell expresses a Notch ligand (belonging to either the Delta or the Serrate/Jagged subfamily) on its surface; this binds to the receptor, Notch, in the membrane of the signal-receiving cell and thereby triggers cleavage of Notch, releasing an intracellular fragment, the Notch intracellular domain (NICD); NICD translocates to the nucleus, where it acts as a transcriptional regulator [1,7] (Figure 1). The main -or at least, the best-studied -targets of direct regulation by NICD are the members of the Hairy/E(spl) family (Hes genes in mammals, her genes in zebrafish) [8,9]; these code for inhibitory basic helix-loop-helix (bHLH) transcriptional A Ab bs st tr ra ac ct tThe Notch signaling pathway has multifarious functions in the organization of the developing vertebrate embryo. One of its most fundamental roles is in the emergence of the regular pattern of somites that will give rise to the musculoskeletal structures of the trunk. The parts it plays in t...

Epb41l5 competes with Delta as a substrate for Mib1 to coordinate specification and differentiation of neurons

“…This conclusion was supported by the observations that there was no obvious increase in neurogenesis marked by expression of ngn1 or deltaA (Fig. S2A-F) and that epb41l5-deficient embryos did not show any problems with formation of somites in the caudal part of the trunk or the tail (data not shown), characteristic features of mutants with loss of Notch signaling (Lewis et al, 2009). …”

Identification and expression analysis of two novel members of the Mesp family in zebrafish

“…, aei/deltaD-/-and wit/mib-/-the segmentation clock is desynchronized and irregular somitic boundaries are made (reviewed in Lewis et al, 2009).…”

Building the backbone: the development and evolution of vertebral patterning

“…Many recent studies have elucidated the molecular mechanisms that control how somite boundaries form, and that regulate the oscillatory gene expression underlying somite formation [comprehensively reviewed by Bénazéraf and Pourquié (2013); Delaune et al (2012); Lewis et al (2009); Oates et al (2012)]. During development, each somite differentiates into the dermomyotome, which forms dermis and skeletal muscle, and the sclerotome, which gives rise to vertebral components and their associated joints.…”