Somite Markers Proteins

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Somite differentiation in zebrafish

Shortly after the C&E movements position the PSM next to the dorsal midline at the end of gastrulation, the first pair of somites forms. In zebrafish, additional somites are generated at 30 min intervals in an anterior to posterior wave until a total of about 30 somite pairs formed alongside the notochord at 24 hpf.

Segmented somites give rise to the vertebrae and muscle of the trunk and tail. Zebrafish somite is predominantly myotome, with sclerotome a relatively minor component. Recent studies suggest that dermomyotome exists in the zebrafish somite as a layer of somitic cells expressing pax3 and pax7 genes, external to the newly formed myotome. During somitogenesis, the sclerotome precursors initially form as a cluster of cells on the ventromedial surface of the somite, and migrate dorsally to encircle the notochord and neural tube. The myotome consists of two classes of muscle fibers: slow muscle fibers, which are mononucleate and reside at the lateral surface of the myotome; and fast muscle fibers, which are polynucleate and constitute the medial portion of the myotome. The fast muscles are derived from the lateral somitic cells that are located in the lateral portion of the somite. The slow muscles originate from the adaxial cells, which are specified as two patches of presomitic cells adjacent to the axial mesoderm during mid-gastrulation. They can be recognized by their distinct cuboidal morphology, notochord-adjacent positions, and early expression of the myogenic factors MyoD and Myf5. Concurrent with the specification of adaxial cells during gastrulation, the axial and presomitic mesoderm undergoes marked C&E movements. Whether C&E gastrulation movements have an influence on the adaxial cell fate remains to be investigated.

During somitogenesis, the adaxial cells undergo dramatic morphological changes to form a single stack of anteroposteriorly-elongated cells flanking the notochord. The majority of the adaxial cells migrates laterally throughout the somite and differentiates into a monolayer of slow muscle fibers at the myotome surface. Some adaxial cells do not migrate, but remain close to the notochord, where they differentiate as so-called “muscle pioneers” that express the Engrailed proteins. The lateral migration of slow muscle cells also initiates a medial-to-lateral wave of fast muscle differentiation and morphogenesis.

Several studies have established that different levels of Hedgehog (Hh) signaling emanating from the axial mesoderm produce different cell types in the zebrafish myotome. High levels of Hh signal induce Engrailed-expressing muscle pioneers and a small subset of fast muscle fibers, the Engrailed-expressing medial fast fibers. Slightly lower levels of Hh signal induce the slow muscle fibers that migrate to the myotome surface. Finally, the lateral somitic cells that receive low levels of Hh are designated to become fast muscles.

The specification of myotomal cell types is also controlled by the time at which cells receive the Hh signal. Early exposure of somitic cells to Hh signal is restricted to the adaxial cells that lie immediately next to the dorsal midline. The gradient of Hh activity within the adaxial cell population is essential for the separation of the precursors of muscle pioneers and migrating slow muscles. It is only after the lateral migration of the slow muscle cells that a subset of lateral somitic cells becomes exposed to the Hh signal; by this time, they are irreversibly committed to the fast lineage and give rise to the medial fast muscles.

Whereas the molecular mechanisms specifying the slow muscle fate are well documented, there is little understanding of how the slow muscle morphogenesis is controlled. Although Hh signal derived from the notochord is critical for the specification and differentiation of slow muscle cells, mutant analyses argue against a role of Hh in the shape change or lateral migration of these cells. A previous report demonstrated that the migration of slow muscle cells follows a dynamic wave of m- and n-cadherin co-expression moving mediolaterally through the developing somite. The large extracellular polysaccharide Hyaluronan and its synthesizing enzymes are also required for the normal slow muscle migration. Aside from these studies, our understanding of the cellular and molecular regulation of zebrafish slow muscle morphogenesis remains incomplete.