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We demonstrate that skeletal stem cells (SSCs) isolated from mice with a gain-of-function D849V point mutation in PDGFR\u03b2 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 PDGFR\u03b2D849V. Mutant cells undergo poor osteogenesis in vitro with increased expression of Sox9 and other chondrogenic markers. Mice with PDGFR\u03b2D849V exhibit osteopenia. Increased STAT5 phosphorylation and overexpression of Igf1 and Socs2 in PDGFR\u03b2D849V cells suggests that overgrowth in mice involves PDGFR\u03b2D849V activating the STAT5-IGF1 axis locally in the skeleton. Our study establishes that PDGFR\u03b2D849V causes osteopenic skeletal phenotypes that are associated with intrinsic changes in SSCs, promoting chondrogenesis over osteogenesis.<\/jats:p>","DOI":"10.1242\/dev.199607","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T12:14:05Z","timestamp":1636114445000},"source":"Crossref","is-referenced-by-count":14,"title":["Skeletal stem cell fate defects caused by <i>Pdgfrb<\/i> activating mutation"],"prefix":"10.1242","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0428-3971","authenticated-orcid":false,"given":"Hae Ryong","family":"Kwon","sequence":"first","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jang H.","family":"Kim","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"},{"name":"Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Woods","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"},{"name":"Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2168-7836","authenticated-orcid":false,"given":"Lorin E.","family":"Olson","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"},{"name":"Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"2021120214363790700_DEV199607C1","doi-asserted-by":"publisher","first-page":"2813","DOI":"10.1101\/gad.1017802","article-title":"The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6","volume":"16","author":"Akiyama","year":"2002","journal-title":"Genes Dev."},{"key":"2021120214363790700_DEV199607C2","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1101\/gad.1171104","article-title":"Interactions between Sox9 and beta-catenin control chondrocyte differentiation","volume":"18","author":"Akiyama","year":"2004","journal-title":"Genes Dev."},{"key":"2021120214363790700_DEV199607C3","doi-asserted-by":"publisher","first-page":"189","DOI":"10.3389\/fcell.2019.00189","article-title":"A revised perspective of skeletal stem cell biology","volume":"7","author":"Ambrosi","year":"2019","journal-title":"Front. 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