Molecular signatures identify immature mesenchymal progenitors in early mouse limb buds that respond differentially to morphogen signaling

The key molecular interactions governing vertebrate limb bud development are a paradigm for studying the mechanisms controlling progenitor cell proliferation and specification during vertebrate organogenesis. However, little is known about the cellular heterogeneity of the mesenchymal progenitors in early limb buds that ultimately contribute to the chondrogenic condensations prefiguring the skeleton. We combined flow cytometric and transcriptome analyses to identify the molecular signatures of several distinct mesenchymal progenitor cell populations present in early mouse forelimb buds. In particular, jagged 1 (JAG1)-positive cells located in the posterior-distal mesenchyme were identified as the most immature limb bud mesenchymal progenitors (LMPs), which crucially depend on SHH and FGF signaling in culture. The analysis of gremlin 1 (Grem1)-deficient forelimb buds showed that JAG1-expressing LMPs are protected from apoptosis by GREM1-mediated BMP antagonism. At the same stage, the osteo-chondrogenic progenitors (OCPs) located in the core mesenchyme are already actively responding to BMP signaling. This analysis sheds light on the cellular heterogeneity of the early mouse limb bud mesenchyme and on the distinct response of LMPs and OCPs to morphogen signaling.This work was supported by funds from both the Universität Basel and the Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030B_166685 to A.Z. and R.Z.; 31003A_156430 to R.Z. and Ivan Martin), by a SystemsX iPhD grant (51PH-0_131349 to E.Ü.), and by the Deutsche Forschungsgemeinschaft (RE 3830/2-1 to R.R.). Deposited in PMC for immediate release