Abstract
How distinct cell fates are manifested by direct lineage ancestry from bipotent progenitors, or by specification of individual cell types is a key question for understanding the emergence of tissues. The interplay between skeletal muscle progenitors and associated connective tissue 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-tracing strategies combined with single cell RNAseq and in situ analyses, we identify bipotent progenitors expressing Myf5 (an upstream regulator of myogenic fate) 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. Disrupting myogenic identity shifts muscle progenitors to a connective tissue fate. The emergence of Myf5-derived connective tissue is associated with the activity of several transcription factors, including Foxp2. Interestingly, this unexpected bifurcation in cell fate was not observed in craniofacial regions that are colonised by neural crest cells. Therefore, we propose that an ancestral bi-fated program gives rise to muscle and connective tissue cells in skeletal muscles that are deprived of neural crest cells.
Highlights
Stromal cells that are associated with skeletal muscles play critical roles in providing structural support and molecular cues (Biferali et al, 2019; Kardon et al, 2003; Sefton and Kardon, 2019)
We propose that an ancestral bi-fated program gives rise to muscle and connective tissue cells in skeletal muscles that are deprived of neural crest cells
Cardiopharyngeal mesoderm, which constitutes the major portion of cranial mesoderm, has cardiovascular potential, which manifests in the embryo as regions of clonally related cardiac and craniofacial skeletal muscles (Diogo et al, 2015; Swedlund and Lescroart, 2019)
Summary
Stromal cells that are associated with skeletal muscles play critical roles in providing structural support and molecular cues (Biferali et al, 2019; Kardon et al, 2003; Sefton and Kardon, 2019). The extent of this contribution was redefined in muscles derived from cranial mesoderm, including extraocular (EOM), laryngeal and pharyngeal muscles (Comai et al, 2020; Grimaldi et al, 2015; Heude et al, 2018; Kuroda et al, 2021; Noden and Epstein, 2010) These muscles contain mesenchyme that is mesoderm-derived in their dorso-medial component, whereas the remaining muscle mass is embedded in mesenchyme that is neural crest-derived. Cardiopharyngeal mesoderm, which constitutes the major portion of cranial mesoderm, has cardiovascular potential, which manifests in the embryo as regions of clonally related cardiac and craniofacial skeletal muscles (Diogo et al, 2015; Swedlund and Lescroart, 2019). While cardiopharyngeal mesoderm was shown to give rise to connective tissues in the mammalian pharynx, the extent of its contribution to other craniofacial muscles in general has not been fully addressed (Adachi et al, 2020)
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