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Previously, we found that a conserved EBAX-type CRL regulates the protein quality of SAX-3\/ROBO guidance receptors in Caenorhabditis elegans. Here, we report that ZSWIM8, the mammalian homolog of EBAX-1, is essential for developmental stability of mammalian brains. Conditional deletion of Zswim8 in the embryonic nervous system causes global cellular stress, partial perinatal lethality and defective migration of neural progenitor cells. CRISPR-mediated knockout of ZSWIM8 impairs spine formation and synaptogenesis in hippocampal neurons. Mechanistic studies reveal that ZSWIM8 controls protein quality of Disabled 1 (Dab1), a key signal molecule for brain development, thus protecting the signaling strength of Dab1. As a ubiquitin ligase enriched with intrinsically disordered regions (IDRs), ZSWIM8 specifically recognizes IDRs of Dab1 through a \u201cdisorder targets misorder\u201d mechanism and eliminates misfolded Dab1 that cannot be properly phosphorylated. Adult survivors of ZSWIM8 CKO show permanent hippocampal abnormality and display severely impaired learning and memory behaviors. Altogether, our results demonstrate that ZSWIM8-mediated PQC is critical for the stability of mammalian brain development.<\/jats:p>","DOI":"10.1093\/cercor\/bhac313","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T02:58:00Z","timestamp":1661137080000},"page":"3866-3881","source":"Crossref","is-referenced-by-count":22,"title":["The ZSWIM8 ubiquitin ligase regulates neurodevelopment by guarding the protein quality of intrinsically disordered Dab1"],"prefix":"10.1093","volume":"33","author":[{"given":"Guan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurobiology\u00a0and\u00a0Department of Neurology of Second Affiliated Hospital , NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; The MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058 , 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