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In this study, using CRISPR\/Cas9-mediated gene knockout and stem Leydig cells (SLCs) transplantation, we identified a critical Dhh\/Patched 2 (Ptch2)\/Glioma-associated oncogene homolog 1 (Gli1)\/steroidogenic factor 1 (Sf1) signaling axis essential for SLC differentiation in Nile tilapia (\n                    <jats:italic>Oreochromis niloticus<\/jats:italic>\n                    ). Dhh deficiency resulted in defective adult Leydig cells and androgen insufficiency. Rescue experiments involving 11-ketotestosterone administration and a Dhh agonist treatment, combined with SLCs transplantation, demonstrated that Dhh regulates SLC differentiation, not survival. In vitro knockout of\n                    <jats:italic>ptch1<\/jats:italic>\n                    and\n                    <jats:italic>ptch2<\/jats:italic>\n                    in SLCs revealed that Ptch2 likely acts as the functional receptor for Dhh. This was further supported by in vivo genetic rescue experiments, where\n                    <jats:italic>ptch2<\/jats:italic>\n                    mutation did not impair testicular development, yet completely rescued the testicular defects in\n                    <jats:italic>dhh<\/jats:italic>\n                    mutants\u2014consistent with Ptch2 acting as an inhibitory receptor whose loss alleviates Dhh pathway suppression. Luciferase assays in Gli-knockout SLCs demonstrated that Gli1 acts as the primary transcriptional effector and transactivates\n                    <jats:italic>sf1<\/jats:italic>\n                    expression. Additionally, functional transplantation assays confirmed that Sf1 is indispensable for SLC differentiation, as Sf1-overexpressing SLCs rescued differentiation, whereas\n                    <jats:italic>sf1<\/jats:italic>\n                    -mutant SLCs failed. Overall, our work delineates the Dhh-Ptch2-Gli1-Sf1 axis and provides fundamental insights into the endocrine regulation of Leydig cell lineage development.\n                  <\/jats:p>","DOI":"10.7554\/elife.109979","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T16:30:16Z","timestamp":1773073816000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.109979","source":"Crossref","is-referenced-by-count":0,"title":["Desert Hedgehog mediates stem Leydig cell differentiation through Ptch2\/Gli1\/Sf1 signaling axis"],"prefix":"10.7554","volume":"15","author":[{"given":"Changle","family":"Zhao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01kj4z117","id-type":"ROR","asserted-by":"publisher"}],"name":"Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City, Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Laboratory of Aquatic Science of Chongqing, School of 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