The vertebrate segmentation clock and its role in skeletal birth defects

Abstract

The segmental structure of the vertebrate body plan is most evident in the axial skeleton. The regulated generation of somites, a process called somitogenesis, underlies the vertebrate body plan and is crucial for proper skeletal development. A genetic clock regulates this process, controlling the timing of somite development. Molecular evidence for the existence of the segmentation clock was first described in the expression of Notch signaling pathway members, several of which are expressed in a cyclic fashion in the presomitic mesoderm (PSM). The Wnt and fibroblast growth factor (FGF) pathways have also recently been linked to the segmentation clock, suggesting that a complex, interconnected network of three signaling pathways regulates the timing of somitogenesis. Mutations in genes that have been linked to the clock frequently cause abnormal segmentation in model organisms. Additionally, at least two human disorders, spondylocostal dysostosis (SCDO) and Alagille syndrome (AGS), are caused by mutations in Notch pathway genes and exhibit vertebral column defects, suggesting that mutations that disrupt segmentation clock function in humans can cause congenital skeletal defects. Thus, it is clear that the correct, cyclic function of the Notch pathway within the vertebrate segmentation clock is essential for proper somitogenesis. In the future, with a large number of additional cyclic genes recently identified, the complex interactions between the various signaling pathways making up the segmentation clock will be elucidated and refined.

Notch pathway regulation of chondrocyte differentiation and proliferation during appendicular and axial skeleton development

“…Several Notch signaling pathway components regulate somite segmentation, which underlies axial skeleton patterning (7). In addition, in vivo Notch pathway overexpression or underexpression in the osteogenic lineage demonstrates that Notch inhibits osteogenic differentiation and growth in the axial and appendicular skeleton (8)(9)(10).…”

Oscillatory lunatic fringe activity is crucial for segmentation of the anterior but not posterior skeleton

“…Furthermore, cyclic gene expression has been described in the presomitic mesoderm for many other genes linked to the Notch signaling pathway in mouse, zebrafish and chick (reviewed by Rida et al, 2004;Shifley and Cole, 2007). The Wnt pathway has also been linked to the clock.…”

Vitamin A Deficiency Induces Congenital Spinal Deformities in Rats

“…Mutations in components of these signaling pathways have been linked to several malformations, including spondylocostal dysostosis (SCDO), Alagille sydrome (AGS), abnormal vertebral segments (hemivertebrae,wedge vertebrae, block vertebrae), spinal deformities, etc. [10,11] Recent findings have suggested that disruption of the retinoic acid (RA) pathway may lead to a loss of left-right bilateral symmetry in mouse embryos [12][13][14]. Thus, we hypothesize that RA signaling pathway may also play a role in the development of segmentation clock that regulates the segmental structure of the vertebrate body plan during embroyogenesis.…”