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

Yan Wang1,2, Kaifan Zhang3, Jin Guo4

  • 1Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 12, 2022
PubMed

Insights

The serine/threonine kinase PAK2 (p21-activated kinase 2) is crucial for neural tube closure. Mutations in PAK2 cause neural tube defects (NTDs) by disrupting BMP signaling and hinge point formation.

Area of Science:

  • Developmental Biology
  • Genetics
  • Cell Biology

Background:

  • Neural tube closure is a complex process, and its failure leads to common birth defects known as neural tube defects (NTDs).
  • The serine/threonine kinase p21-activated kinase 2 (PAK2) regulates cytoskeleton dynamics, but its specific role in neurulation and NTD pathogenesis is not well understood.

Purpose of the Study:

  • To investigate the role of PAK2 in the process of neurulation and its involvement in the development of neural tube defects.
  • To identify the molecular mechanisms by which PAK2 influences neural tube closure and to explore the impact of PAK2 mutations in human NTDs.

Main Methods:

  • Analysis of Pak2 knockout mouse embryos to observe neurulation phenotypes and signaling pathways.
  • Single-cell transcriptome analysis to identify transcriptional changes during neural tube development in Pak2-deficient embryos.
  • Identification and characterization of PAK2 mutations in human NTD fetuses and functional assessment in zebrafish models.

Main Results:

  • Pak2 knockout mouse embryos exhibit craniorachischisis, a severe NTD phenotype, due to the failure in forming dorsolateral hinge points (DLHPs).
  • Pak2 deficiency leads to activated BMP signaling, abnormal cell differentiation, and altered transcriptional events during neural tube development.
  • Mutations in the PAK2 gene were identified in human NTD fetuses, correlating with reduced PAK2 expression and increased BMP signaling in the brain.
  • PAK2 directly regulates Smad9 phosphorylation, inhibiting BMP signaling to promote DLHP formation. Pak2a depletion in zebrafish causes neural tube defects, partially rescued by wild-type PAK2.

Conclusions:

  • PAK2 plays a conserved and critical role in vertebrate neurulation, essential for proper neural tube closure.
  • Mutations in PAK2 are implicated in the molecular pathogenesis of human neural tube defects through disruption of BMP signaling pathways.
  • PAK2 is a key regulator of DLHP formation, and its dysfunction presents a significant mechanism underlying NTDs.
Keywords:
BMP signalingPAK2dorsolateral hinge pointsneural tube defectssingle-cell transcriptome

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