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Here, we developed a primary, immune-competent zebrafish model to study uveal melanoma (UM) using choroidal melanocyte-targeted injection and electroporation of plasmids encoding human GNAQ\n                  <jats:sup>Q209L<\/jats:sup>\n                  together with CRISPR\/Cas9 cassettes for somatic tumor suppressor gene deletion. Single-cell transcriptional profiling of primary melanocytes and melanoma derived from the eye and skin revealed distinct transcriptional programs, with epithelial-to-mesenchymal transition pathways enriched in ocular tumors. In addition, choroidal fibroblasts from tumor-bearing eyes exhibited marked transcriptional changes, including increased fibronectin and collagen expression, consistent with stromal remodeling. Given prior associations between\n                  <jats:italic>mitfa<\/jats:italic>\n                  loss and accelerated GNAQ\n                  <jats:sup>Q209L<\/jats:sup>\n                  tumor onset, the model was applied to determine whether melanocyte differentiation state contributes to the emergence of GNAQ-driven tumors. The increased susceptibility resulted from expansion of Mitfa-independent melanocyte progenitor populations in germline\n                  <jats:italic>mitfa<\/jats:italic>\n                  mutant zebrafish, rather than somatic\n                  <jats:italic>mitfa<\/jats:italic>\n                  loss in differentiated melanocytes, as conditional, melanocyte-specific\n                  <jats:italic>mitfa<\/jats:italic>\n                  deletion in adult zebrafish did not accelerate tumor growth. Furthermore,\n                  <jats:italic>pax3a<\/jats:italic>\n                  -positive melanocyte progenitor cells in\n                  <jats:italic>mitfa<\/jats:italic>\n                  -deficient zebrafish embryos and adult eyes and skin were highly susceptible to transformation induced by GNAQ\n                  <jats:sup>Q209L<\/jats:sup>\n                  but not BRAF\n                  <jats:sup>V600E<\/jats:sup>\n                  . Analogous\n                  <jats:italic>PAX3<\/jats:italic>\n                  positive populations were also identified in mouse and human single-cell transcriptomic datasets. Collectively, these findings establish a critical role for Mitfa-independent melanocyte progenitors in UM pathogenesis.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of Significance<\/jats:title>\n                  <jats:p>\n                    Choroid-targeted GNAQ\n                    <jats:sup>Q209L<\/jats:sup>\n                    expression induces anatomically correct uveal melanoma in adult zebrafish, with germline\n                    <jats:italic>mitfa<\/jats:italic>\n                    deletion expanding mitfa-independent melanocyte progenitors with enhanced susceptibility that are transcriptionally distinct from the subpopulation transformed by BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.05.652300","type":"posted-content","created":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T01:40:10Z","timestamp":1746841210000},"source":"Crossref","is-referenced-by-count":0,"title":["GNAQ Induces Melanomagenesis in Mitfa-Independent Melanocyte Progenitors in a Zebrafish Model of Uveal Melanoma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6482-2279","authenticated-orcid":false,"given":"Julius I.","family":"Yevdash","sequence":"first","affiliation":[{"name":"Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delaney","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katelyn R.","family":"Campbell-Hanson","sequence":"additional","affiliation":[{"name":"Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Gutelius","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Boston University School of Medicine, Boston, MA, 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen P. G.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Boston University School of Medicine, Boston, MA, 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan","family":"Friend","sequence":"additional","affiliation":[{"name":"Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"O\u2019Toole","sequence":"additional","affiliation":[{"name":"Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brynnon E","family":"Harman","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242, Iowa"},{"name":"Institute for Vision Research, University of Iowa, Iowa City, IA 52242, 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