Right Place, Right Time: BMP’s role in vertebrate sclerotome development
Summary by Leanne Iannucci: Linjun Xie, Roger C. Ma, Katrinka M. Kocha, Emilio E. Méndez-Olivos, Peng Huang; Dynamic BMP signaling regulates sclerotome induction and lineage diversification in zebrafish. Development. 2025; 152 (12): dev204321. https://doi.org/10.1242/dev.204321
Image credit: Wikimedia Commons (DataBase Center for Life Science (DBCLS))
The bone morphogenetic protein (BMP) signaling pathway plays an important role in vertebrate development. BMP is involved in some of the earliest cell fate decisions (e.g. dorsal-ventral axis patterning) and continues to play a decision making-role in different contexts extending into later developmental stages and adulthood. One case where it has been implicated, but remains incompletely understood, is in zebrafish somite development. The somite is a segment of primitive tissue in developing vertebrates that exists only transiently; it eventually subdivides into different compartments that become the dermis (dermatome), muscles (myotome), and axial skeleton (sclerotome). The sclerotome sub-compartment itself will give rise to different types of fibroblast populations: the axial tendon cells or tenocytes, notochord-adjacent cells, and fin mesenchymal cells. In this work, Xie et al. ask: What role does BMP signaling play in specifying these different cell fates contained within the sclerotome?
First, the authors wanted to verify BMP as a major player in sclerotome induction. They first confirmed that the BMP machinery (e.g. ligands, receptors, activated effectors) is present in the somite at the time of sclerotome induction. Then, they leveraged gain- and loss-of-function genetic tools that allowed the authors to alter BMP signaling throughout the organism at a specific time (e.g., when the sclerotome is being specified). Through these experiments, they were able to see that increasing BMP signaling led to an expansion of the sclerotome and reduction of other somite compartments (the “dermomyotome”); the converse was true when BMP was reduced. These findings led them to conclude that BMP is both necessary and sufficient for sclerotome formation.
Next, they wanted to see if BMP signaling changed as the sclerotome developed: did unique subpopulations of cells derived from the sclerotome continue to similarly experience BMP signaling? They observed that the fin mesenchyme remained BMP active whereas the notochord-adjacent sclerotome cells stopped experiencing BMP signaling. But is this change in signaling required for these two different cell fates to specify correctly? They performed gain- and loss-of-function experiments to address this question. When BMP was overexpressed, they saw a loss of maturity markers in axial tenocytes which are derived from the notochord-adjacent sclerotome cells. If BMP was inhibited, the sclerotome-derived fin mesenchymal cells had an abnormal hyperbranching phenotype. These findings led the authors to conclude that regulation of BMP in different sclerotome-derived sub-compartments is crucial for the proper formation of its diverse cell sub-populations.
The authors posit an interesting relationship between space and time in the sclerotome: mechanisms controlling the timing of BMP signaling help define location-specific cell types. A similar phenomenon is observed in early gastrulation: cells on opposite sides of the developing embryo experience unique levels and timings of BMP signaling that lead to the establishment of the dorsal-ventral axis. Dynamic regulation of BMP is thus crucial and carefully controlled throughout development. What other players are involved in regulating BMP signaling dynamics and how we can best use this knowledge as a framework for regenerative approaches to human health remain open questions in the field.