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The orphan G protein-coupled receptor Gpr161 localizes to primary cilia and functions as a negative regulator of Shh signaling by promoting Gli transcriptional repressor versus activator formation. Here, we show that forelimb buds are not formed in Gpr161 knockout mouse embryos despite establishment of prospective limb fields. Limb-specific deletion of Gpr161 resulted in prematurely expanded Shh signaling and ectopic Shh-dependent patterning defects resulting in polysyndactyly. In addition, endochondral bone formation in forearms, including formation of both trabecular bone and bone collar was prevented. Endochondral bone formation defects resulted from accumulation of proliferating round\/periarticular-like chondrocytes, lack of differentiation into columnar chondrocytes, and corresponding absence of Ihh signaling. Gpr161 deficiency in craniofacial mesenchyme also prevented intramembranous bone formation in calvarium. Defects in limb patterning, endochondral and intramembranous skeletal morphogenesis were suppressed in the absence of cilia. Overall, Gpr161 promotes forelimb formation, regulates limb patterning, prevents periarticular chondrocyte proliferation and drives osteoblastogenesis in intramembranous bones in a cilium-dependent manner.<\/jats:p>","DOI":"10.1242\/dev.154054","type":"journal-article","created":{"date-parts":[[2018,1,9]],"date-time":"2018-01-09T01:10:31Z","timestamp":1515460231000},"source":"Crossref","is-referenced-by-count":62,"title":["The G protein-coupled receptor Gpr161 regulates forelimb formation, limb patterning and skeletal morphogenesis in a primary cilium-dependent manner"],"prefix":"10.1242","volume":"145","author":[{"given":"Sun-hee","family":"Hwang","sequence":"first","affiliation":[{"name":"UT Southwestern Medical Center 1 Department of Cell Biology , , Dallas, Texas , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin A.","family":"White","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center 2 Internal Medicine , , Dallas, Texas , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bandarigoda N.","family":"Somatilaka","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center 1 Department of Cell Biology , , Dallas, Texas , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Shelton","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center 2 Internal Medicine , , Dallas, Texas , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Richardson","sequence":"additional","affiliation":[{"name":"Pathology, UT Southwestern Medical Center 3 , Dallas, Texas , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4790-3090","authenticated-orcid":false,"given":"Saikat","family":"Mukhopadhyay","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center 1 Department of Cell Biology , , Dallas, Texas , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2018,1,8]]},"reference":[{"key":"2024061216123007100_DEV154054C1","doi-asserted-by":"publisher","first-page":"3133","DOI":"10.1242\/dev.002709","article-title":"Regulation of skeletogenic differentiation in cranial dermal bone","volume":"134","author":"Abzhanov","year":"2007","journal-title":"Development"},{"key":"2024061216123007100_DEV154054C2","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1242\/dev.00191","article-title":"Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo","volume":"130","author":"Agarwal","year":"2003","journal-title":"Development"},{"key":"2024061216123007100_DEV154054C3","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1083\/jcb.201607095","article-title":"Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins","volume":"216","author":"Badgandi","year":"2017","journal-title":"J. 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