RESUMO
Autosomal dominant PDGFRß gain-of-function mutations in mice and humans cause a spectrum of wasting and overgrowth disorders afflicting the skeleton and other connective tissues, but the cellular origin of these disorders remains unknown. We demonstrate that skeletal stem cells (SSCs) isolated from mice with a gain-of-function D849V point mutation in PDGFRß exhibit colony formation defects that parallel the wasting or overgrowth phenotypes of the mice. Single-cell RNA transcriptomics with SSC-derived polyclonal colonies demonstrates alterations in osteogenic and chondrogenic precursors caused by PDGFRßD849V. Mutant cells undergo poor osteogenesis in vitro with increased expression of Sox9 and other chondrogenic markers. Mice with PDGFRßD849V exhibit osteopenia. Increased STAT5 phosphorylation and overexpression of Igf1 and Socs2 in PDGFRßD849V cells suggests that overgrowth in mice involves PDGFRßD849V activating the STAT5-IGF1 axis locally in the skeleton. Our study establishes that PDGFRßD849V causes osteopenic skeletal phenotypes that are associated with intrinsic changes in SSCs, promoting chondrogenesis over osteogenesis.
Assuntos
Mutação com Ganho de Função , Mioblastos Esqueléticos/metabolismo , Mutação Puntual , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Substituição de Aminoácidos , Animais , Condrogênese/genética , Regulação da Expressão Gênica , Camundongos , Camundongos Transgênicos , Mioblastos Esqueléticos/patologia , Osteogênese/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais/genéticaRESUMO
Specific cell targeting with one site-specific recombinase is challenging. In this issue of Cell Stem Cell, Han et al. (2021) released a collection of Dre drivers and demonstrate how two recombinases can be combined to improve the cell specificity of lineage tracing and gene inactivation in mice.