Somitogenesis

The segmentation process is driven by WNY signaling, FGF signaling, and especially the Notch signaling (reviewed in Dunwoodie et al. 2009, Ferjentsik et al. 2009), Hubaud and Pourquie 2014). The intersection of posterior-anterior gradients of WNT and FGF signaling and an anterior-posterior gradient of retinoic acid signaling regulates the position of somite boundaries as perturbation of any of the gradients affects somite boundaries (reviewed in Gibb et al. 2010, Hubard and Pourquie et al. 2014). Thus WNT, FGF, and retinoic acid appear to form the wavefront, also called the determination front. Segmentation periodicity is controlled by HES7-mediated negative feedback loops in the Notch pathway, which constitute a molecular oscillator or segmentation clock. Activation of LFNG expression by Notch and inhibition of Notch signaling by LFNG, possibly via regulation of the DLL3 ligand, constitute another negative feedback loop that acts as a molecular oscillator. Clock oscillations are initiated in nascent presomitic mesoderm in the primitive streak of the gastrulating embryo and posterior-to-anterior waves sweep to anterior paraxial mesoderm to regulate MESP2/RIPPLY2 expression to initiate segmentation. MESP2 activates expression of EPHA4, an Eph receptor that participates in segment boundary formation. MESP2 also activates expression of RIPPLY2, an inhibitor of TBX6. TBX6 is an activator of MESP2, therefore MESP2 indirectly inhibits its own expression via RIPPLY2.

Mutations in components of the segmentation clock, for example DLL3, MESP2, LFNG, and HES7, cause congenital vertebral defects in humans.