During embryonic development, undifferentiated progenitor cells balance the generation of additional progenitor cells with differentiation. Within the developing limb, cartilage cells differentiate from mesodermal progenitors in an ordered process that results in the specification of the correct number of appropriately sized skeletal elements. The internal pathways by which these cells maintain an undifferentiated state while preserving their capacity to differentiate is unknown. Here, we report that the arginine methyltransferase PRMT5 has a crucial role in maintaining progenitor cells. Mouse embryonic buds lacking PRMT5 have severely truncated bones with wispy digits lacking joints. This novel phenotype is caused by widespread cell death that includes mesodermal progenitor cells that have begun to precociously differentiate into cartilage cells. We propose that PRMT5 maintains progenitor cells through its regulation of Bmp4. Intriguingly, adult and embryonic stem cells also require PRMT5 for maintaining pluripotency, suggesting that similar mechanisms might regulate lineage-restricted progenitor cells during organogenesis.
Author contributions
J.L.N., Q.L., D.D., Z.J., S.M., M.T.B., A.G., H.J. and S.A.V. designed the experiments. J.L.N., Q.L., S.C., J.C.U., B.-L.H., D.D., Z.J. and A.G. conducted the experiments. J.L.N., D.D., Z.J., H.J. and S.A.V. wrote the manuscript with input from all authors.
Funding
This work was supported by the National Institutes of Health [R01HD073151 to S.A.V.] and Cancer Prevention Research Institute of Texas [#RP120343 to S.A.V.]. Deposited in PMC for release after 12 months.
Data availability
RNA-seq datasets for Prmt5 cKO versus control forelimbs are available at Gene Expression Omnibus under accession number GSE79487.
