The main progress in understanding the genetic basis of SDV has come through the study of somitogenesis in animal models , mainly mouse but also chick. Animals with specific gene knockouts are generated and multiple gene expression assays undertaken to help elucidate the developmental pathways. Somitogenesis is the sequential process whereby paired blocks of paraxial mesoderm are patterned and laid down on either side of the midline from the presomitic mesoderm (PSM) to form somites, a process that takes place between days 20–32 of human embryonic development, proceeding in a rostro-caudal direction. In mouse, a pair of somites is formed every 1–3 h, whilst in humans the process is estimated to take 6–12 h based on cell culture models and analysis of staged anatomical collections [8, 9]. Somites ultimately give rise to four substructures—sclerotome , which forms the axial skeleton and ribs; dermotome, which forms the dermis; myotome, which forms the axial musculature and syndetome, which forms the tendons [10, 11]. Somitogenesis begins shortly after gastrulation and continues until the pre-programmed number of somite blocks is formed. In man 31 blocks of paired tissue are formed but the number is species-specific. The establishment of somite boundaries takes place as a result of very finely tuned molecular processes determined by activation and negative feedback interactions between components of the Notch, Wnt and FGF signaling pathways [12, 13] (Fig. 7.1). In the rostral third of the PSM formation of segmental boundaries is subject to levels of the factor FGF8, which is produced in the caudal region of the embryo [14] and which probably maintains cells in an immature state until levels fall below a threshold, allowing boundary formation. Somites already harbour specification toward their eventual vertebral identity, a process regulated by the Hox family of transcription factors [15], which also display oscillatory expression in the mouse during somitogenesis [16].

The Wnt signalling pathway also displays oscillatory expression in a different temporal phase from Notch pathway genes, and plays a key role in the segmentation clock [17–19]. The mediators of the determination front and the segmentation clock (Notch, FGF, Wnt) are required for forming the somite boundary and specify rostro-caudal patterning of presumptive somites, for which Mesp2 is crucial [20]. Mesp2 is expressed caudal to the somite which is forming and this domain is set where Notch signalling is active, FGF signalling is absent, and the transcription factor Tbx6 is expressed. Precise periodicity in the establishment of somite blocks is mediated by several so-called ‘cycling’, or ‘oscillatory’, genes, two of which, LFNG and HES7, are implicated in human SCD.

Somites themselves, having formed, are subsequently partitioned into rostral and caudal compartments, with vertebrae formed from the caudal compartment of one somite and the adjacent rostral compartment of the next, a phenomenon that is known as ‘resegmentation’ [21–24]. An understanding of the molecular biology of somitogenesis in animal models, in combination with finding patients and families with specific forms, or patterns, of segmentation anomalies, has led to the most definitive progress in understanding the causes of rare mendelian forms of SDV. Ongoing research is identifying more cycling genes and pathways involved in the regulation of somitogenesis .