Skeletal tissues originate from paraxial mesoderm, lateral plate mesoderm, and neural crest. Paraxial mesoderm is produced by invagination of cells through the primitive streak and is the precursor of somites, which are spheres of mesenchyme bounded by epithelium that bud at fixed intervals from the anterior paraxial mesoderm in a process termed somitogenesis (reviewed in Tam and Trainor 1994, Pourquie 2003). Somites give rise to the axial skeleton and skeletal muscles.
Paraxial mesoderm becomes specified at a lower level of BMP signaling (Xi et al. 2017) that results from the interaction of BMP4, produced by the lateral plate mesoderm, with NOGGIN (NOG), a negative regulator of BMP signaling produced by the notochord (reviewed in Tani et al. 2020). WNT signaling by WNT3A that activates beta‑catenin (CTNNB1), FGF signaling that acts though FGFR1, and TBXT activate expression of TBX6 and Mesogenin 1 (MSGN1). MSGN1 binds and activates SNAI1 to promote epithelial-mesenchymal transitions (EMT). TBX6 activates MSGN1, and MSGN1 activates TBX6, to establish a positive feedback loop that ensures commitment to the paraxial mesoderm lineage. TBX6 and MSGN1 act with WNT signaling to activate expression of MSGN1, and the NOTCH ligand Delta‑like 1 (DLL1), which enhances NOTCH signaling. MSGN1 binds and activates expression of DLL1, DLL3, NOTCH1, and NOTCH2, and binds to Clock enhancers that regulate periodic expression of LFNG during somitogenesis in the anterior paraxial mesoderm. The counterbalancing DLL3 protein inhibits NOTCH signaling by binding NOTCH1 in endosomes and targeting NOTCH1 for lysosomal degradation.
TBX6 alone is capable of reprogramming pluripotent stem cells to paraxial mesoderm (Sadahiro et al. 2018) and acts in a regulatory loop with MESP2 to create the boundaries of nascent somites (Oginuma et al. 2011): TBX6 activates expression of MESP2 which then represses TBX6 by targeting TBX6 for degradation, leaving MESP2 alone at the segmental boundary.