Loss-of-Function of p21-Activated Kinase 2 Links BMP Signaling to Neural Tube Patterning Defects.
Yan WangKaifan ZhangJin GuoShuyan YangXiaohui ShiJinrong PanZheng SunJizhen ZouYi LiYuanyuan LiTianda FanWei SongFang ChengCheng ZengJinchen LiTing ZhangZhong Sheng SunPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2022)
Closure of the neural tube represents a highly complex and coordinated process, the failure of which constitutes common birth defects. The serine/threonine kinase p21-activated 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 Pak2 -/- mouse embryos fail to develop dorsolateral hinge points (DLHPs) and exhibit craniorachischisis, a severe phenotype of NTDs. Pak2 knockout activates BMP signaling that involves in vertebrate bone formation. Single-cell transcriptomes reveal abnormal differentiation trajectories and transcriptional events in Pak2 -/- mouse embryos during neural tube development. Two nonsynonymous and one recurrent splice-site mutations in the PAK2 gene are identified in five human NTD fetuses, which exhibit attenuated PAK2 expression and upregulated BMP signaling in the brain. Mechanistically, PAK2 regulates Smad9 phosphorylation to inhibit BMP signaling and ultimately induce DLHP formation. Depletion of pak2a in zebrafish induces defects in the neural tube, which are partially rescued by the overexpression of wild-type, but not mutant PAK2. The findings demonstrate the conserved role of PAK2 in neurulation in multiple vertebrate species, highlighting the molecular pathogenesis of PAK2 mutations in NTDs.
Keyphrases
- single cell
- protein kinase
- mesenchymal stem cells
- wild type
- endothelial cells
- genome wide
- poor prognosis
- rna seq
- dna methylation
- tyrosine kinase
- pregnant women
- epithelial mesenchymal transition
- oxidative stress
- early onset
- single molecule
- white matter
- signaling pathway
- subarachnoid hemorrhage
- drug induced
- preterm birth
- heat stress