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The mechanisms of ASD are complex and are not yet fully understood, although many ASD risk genes and mouse models have been reported. It has been suggested that deletion of <jats:italic>PRRG4<\/jats:italic> (proline-rich and Gla domain 4) deletion may contribute to autism symptoms in patients with WAGR (Wilms\u2019 tumor, aniridia, gonadoblastoma, mental retardation) syndrome. The mouse model with <jats:italic>PRRG4<\/jats:italic> gene deletion has not been reported so far. This study investigated whether brain-specific conditional knockout of <jats:italic>PRRG4<\/jats:italic> induces ASD-like symptoms in mice by crossing the <jats:italic>PRRG4<\/jats:italic>\n              <jats:sup>fl\/fl<\/jats:sup> mice with <jats:italic>Emx1-Cre<\/jats:italic> mice, which express <jats:italic>Cre<\/jats:italic> in the cerebral cortex and hippocampus.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The <jats:italic>PRRG4<\/jats:italic> brain-specific knockout (<jats:italic>PRRG4<\/jats:italic>\n              <jats:sup>fl<\/jats:sup>\/<jats:sup>fl<\/jats:sup>-<jats:italic>Cre<\/jats:italic>\n              <jats:sup>+<\/jats:sup>, <jats:italic>PRRG4<\/jats:italic>-CKO) mice exhibited social deficits, repetitive behaviors, and anxiety-like symptoms compared to <jats:italic>PRRG4<\/jats:italic>\n              <jats:sup>fl\/fl<\/jats:sup> control mice according to the results of various behavioral tests. <jats:italic>PRRG4<\/jats:italic> knockout led to the increase in total dendritic length, branching, and dendritic spine density in the pyramidal neurons of the cerebral cortex and hippocampus, as well as enhanced levels of synaptic proteins including SYP and PSD95. Immunoprecipitation experiment with PRRG4 antibodies showed dramatic decreased interaction of PRRG4 and MAGI2 proteins in brain tissues from <jats:italic>PRRG4<\/jats:italic>-CKO mice compared to <jats:italic>PRRG4<\/jats:italic>\n              <jats:sup>fl\/fl<\/jats:sup> control mice. GST-RBD pull-down assay showed a significant decrease in RhoA-GTP levels in the cerebral cortex and hippocampus of <jats:italic>PRRG4<\/jats:italic>-CKO mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Brain-specific conditional knockout of the <jats:italic>PRRG4<\/jats:italic> in mice leads to ASD-like symptoms. PRRG4 protein may regulate dendritic and synaptic development in mice by activating RhoA through interaction with MAGI2. These findings provide evidence for a comprehensive understanding of PRRG4 function in vivo and support the association between <jats:italic>PRRG4<\/jats:italic> loss and ASD phenotypes observed in WAGR syndrome.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12575-025-00280-7","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T09:35:50Z","timestamp":1747388150000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PRRG4 Brain-Specific Conditional Knockout Mice Display Autism Spectrum Disorder-Like Behaviors"],"prefix":"10.1186","volume":"27","author":[{"given":"Luxi","family":"Shen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuping","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeyao","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzhi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haihua","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"issue":"2","key":"280_CR1","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1001\/jama.2022.23661","volume":"329","author":"T Hirota","year":"2023","unstructured":"Hirota T, King BH. 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