Somitogenesis

Somitogenesis is the process by which somites are produced. Somites are bilaterally paired blocks of mesoderm that form along the anterior-posterior axis of the developing embryos of segmented animals, often originating in an anterior to posterior direction. In vertebrates, somites give rise to skeletal muscles, trunk skeleton and dermis, and form from presomitic mesoderm (PSM). Different organisms have different numbers of somites, for example frogs have ~10, humans have 33, fish have ~48, and snakes have more than 300. Somitogenesis is an active area of investigation in many laboratories.

The PSM region from which somites arise in vertebrates is also called paraxial mesoderm because of its position flanking the notochord and extending along the anterior-posterior axis of the developing organism. Fate mapping experiments at the blastula stage show PSM progenitors at the marginal zone/primitive streak (depending on the organism), in regions flanking the organizer. Transplant experiments show that only at the late gastrula stage are these cells committed to PSM, meaning that fate determination is tightly controlled by local signals and is not predetermined. For instance, exposure of PSM to Bone Morphogenetic Proteins (BMPs) ventralizes the tissue, however in vivo, BMP antagonists secreted by the organizer (such as noggin and chordin) prevent this and thus promote the formation of dorsal structures.

Once PSM cells have been placed by cell migration during gastrulation, oscillatory expression of many genes begins in these cells as if a developmental clock has been set. These genes include members of the FGF family, Wnt and Notch pathway, as well as targets of these pathways. Somitogenesis is thought to occur via a “clock and wavefront” model, in which largely cell autonomous oscillations in a network of genes and gene products causes cells to oscillate between a permissive and a non-permissive state in a consistently timed fashion like a clock. The wavefront consists of opposing Wnt/FGF and retinoic acid gradients which progresses slowly in an anterior to posterior direction. As the wavefront of signaling comes in contact with cells in the permissive state, they undergo a mesenchymal-epithelial transition and pinch off from the more posterior PSM, forming a somite boundary, resetting the process for the next somite. Intrinsic expression of “clock genes” must oscillate with a periodicity equal to the time necessary for one somite to form, for example 30 minutes in zebrafish, 90 minutes in chicks, 100 minutes in snakes.

Gene oscillation in presomitic cells is not completely cell autonomous. When Notch signaling is disrupted in zebrafish, neighboring cells no longer oscillate synchronously, indicating that Notch signaling is important for keeping neighboring populations of cells synchronous. In addition, when the notochord is ablated during somitogenesis in the chick embryo, the proper number of somites form, but the segmentation clock is delayed for the posterior two thirds of the somites. The anterior somites are not affected. This phenotype was mimicked by addition of Sonic hedgehog (Shh) inhibitors, and timely somite formation was rescued by exogenous Shh protein, showing that the missing signal produced by the notochord is mediated by Shh. Although expression of Shh pathway proteins has not been reported to oscillate in the PSM, they are expressed within the PSM during somitogenesis.