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G protein-coupled receptors (GPCRs) are currently the largest family of membrane receptors targeted by FDA-approved drugs, but there remain many unexplored receptors, including orphan GPCRs with no known biological ligand or physiological function. Thus, we sought to illuminate the cadre of GPCRs expressed at high levels in lymphatic endothelial cells and identified four orphan receptors: GPRC5B, AGDRF5\/GPR116, FZD8 and GPR61. Compared to blood endothelial cells, GPRC5B is the most abundant GPCR expressed in cultured human lymphatic endothelial cells (LECs), and in situ RNAscope shows high mRNA levels in lymphatics of mice. Using genetic engineering approaches in both zebrafish and mice, we characterized the function of GPRC5B in lymphatic development. Morphant gprc5b zebrafish exhibited failure of thoracic duct formation, and Gprc5b\u2212\/\u2212 mice suffered from embryonic hydrops fetalis and hemorrhage associated with subcutaneous edema and blood-filled lymphatic vessels. Compared to Gprc5+\/+ littermate controls, Gprc5b\u2212\/\u2212 embryos exhibited attenuated developmental lymphangiogenesis. During the postnatal period, ~30% of Gprc5b\u2212\/\u2212 mice were growth-restricted or died prior to weaning, with associated attenuation of postnatal cardiac lymphatic growth. In cultured human primary LECs, expression of GPRC5B is required to maintain cell proliferation and viability. Collectively, we identify a novel role for the lymphatic-enriched orphan GPRC5B receptor in lymphangiogenesis of fish, mice and human cells. Elucidating the roles of orphan GPCRs in lymphatics provides new avenues for discovery of druggable targets to treat lymphatic-related conditions such as lymphedema and cancer.<\/jats:p>","DOI":"10.3390\/ijms23105712","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T13:56:12Z","timestamp":1653054972000},"page":"5712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Orphan G-Protein Coupled Receptor GPRC5B Is Critical for Lymphatic Development"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3046-2535","authenticated-orcid":false,"given":"Wenjing","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan P.","family":"Nelson-Maney","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3142-4071","authenticated-orcid":false,"given":"L\u00e1szl\u00f3","family":"B\u00e1lint","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyouk-Bum","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reema B.","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle C. M.","family":"Dy","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Dunleavey","sequence":"additional","affiliation":[{"name":"Tumor Angiogenesis Unit, Mouse Cancer Genetics Program, National Cancer Institute\u2013Frederick, NIH, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brad","family":"St. Croix","sequence":"additional","affiliation":[{"name":"Tumor Angiogenesis Unit, Mouse Cancer Genetics Program, National Cancer Institute\u2013Frederick, NIH, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Caron","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1172\/JCI71603","article-title":"Lymphangiogenic Factors, Mechanisms, and Applications","volume":"124","author":"Zheng","year":"2014","journal-title":"J. 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