2. Academic Validation
  3. Loss-of-Function of p21-Activated Kinase 2 Links BMP Signaling to Neural Tube Patterning Defects

Loss-of-Function of p21-Activated Kinase 2 Links BMP Signaling to Neural Tube Patterning Defects

  • Adv Sci (Weinh). 2022 Dec 11;e2204018. doi: 10.1002/advs.202204018.
Yan Wang 1 2,  Kaifan Zhang 3,  Jin Guo 4,  Shuyan Yang 4,  Xiaohui Shi 1 2,  Jinrong Pan 1 2,  Zheng Sun 1 2,  Jizhen Zou 4,  Yi Li 3,  Yuanyuan Li 1 2,  Tianda Fan 3,  Wei Song 1 2,  Fang Cheng 3,  Cheng Zeng 1 2,  Jinchen Li 5,  Ting Zhang 4,  Zhong Sheng Sun 1 2 3 6
Affiliations

Affiliations

  • 1 Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China.
  • 2 CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 4 Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China.
  • 5 Bioinformatics Center & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China.
  • 6 State Key Laboratory of Integrated Management of Pest Insects and Rodents, Chinese Academy of Sciences, Beijing, 100101, China.
PMID: 36504449 DOI: 10.1002/advs.202204018
Abstract

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.

Keywords

BMP signaling; PAK2; dorsolateral hinge points; neural tube defects; single-cell transcriptome.

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