Identification of bipotent progenitors that give rise to myogenic and connective tissues in mouse

ABSTRACT How distinct cell fates are manifested by direct lineage ancestry from bipotent progenitors, or by specification of individual cell types within a field of cells is a key question for understanding the emergence of tissues. The interplay between skeletal muscle progenitors and associated connective tissues cells provides a model for examining how muscle functional units are established. Most craniofacial structures originate from the vertebrate-specific neural crest cells except in the dorsal portion of the head, where they arise from cranial mesoderm. Here, using multiple lineage-traced single cell RNAseq, advanced computational methods and in situ analyses, we identify Myf5+ bipotent progenitors that give rise to both muscle and juxtaposed connective tissue. Following this bifurcation, muscle and connective tissue cells retain complementary signalling features and maintain spatial proximity. Interruption of upstream myogenic identity shifts muscle progenitors to a connective tissue fate. Interestingly, Myf5-derived connective tissue cells, which adopt a novel regulatory signature, were not observed in ventral craniofacial structures that are colonised by neural crest cells. Therefore, we propose that an ancestral program gives rise to bifated muscle and connective tissue cells in skeletal muscles that are deprived of neural crest.