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The serine\/threonine kinase p21\u2010activated kinase 2 (PAK2) is a critical regulator of cytoskeleton dynamics; however, its role in the neurulation and pathogenesis of neural tube defects (NTDs) remains unclear. Here, the results show that <jats:italic>Pak2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse embryos fail to develop dorsolateral hinge points (DLHPs) and exhibit craniorachischisis, a severe phenotype of NTDs. <jats:italic>Pak2<\/jats:italic> knockout activates BMP signaling that involves in vertebrate bone formation. Single\u2010cell transcriptomes reveal abnormal differentiation trajectories and transcriptional events in <jats:italic>Pak2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse embryos during neural tube development. Two nonsynonymous and one recurrent splice\u2010site mutations in the <jats:italic>PAK2<\/jats:italic> gene are identified in five human NTD fetuses, which exhibit attenuated <jats:italic>PAK2<\/jats:italic> expression and upregulated BMP signaling in the brain. Mechanistically, PAK2 regulates Smad9 phosphorylation to inhibit BMP signaling and ultimately induce DLHP formation. Depletion of <jats:italic>pak2a<\/jats:italic> in zebrafish induces defects in the neural tube, which are partially rescued by the overexpression of wild\u2010type, but not mutant <jats:italic>PAK2<\/jats:italic>. The findings demonstrate the conserved role of PAK2 in neurulation in multiple vertebrate species, highlighting the molecular pathogenesis of <jats:italic>PAK2<\/jats:italic> mutations in NTDs.<\/jats:p>","DOI":"10.1002\/advs.202204018","type":"journal-article","created":{"date-parts":[[2022,12,11]],"date-time":"2022-12-11T21:33:05Z","timestamp":1670794385000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Loss\u2010of\u2010Function of p21\u2010Activated Kinase 2 Links BMP Signaling to Neural Tube Patterning Defects"],"prefix":"10.1002","volume":"10","author":[{"given":"Yan","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Institutes of Life Science Chinese Academy of Sciences  Beijing 100101 China"},{"name":"CAS Center for Excellence in Biotic Interactions University of Chinese Academy of Sciences  Beijing 100049 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