Dual Mechanism Underlying Failure of Neural Tube Closure in the Zic2 Mutant Mouse

Overview

Journal Dis Model Mech

Specialty General Medicine

Date 2023 Mar 14

PMID 36916392

Authors

Sarah Escuin

Saba Rose Raza-Knight

Dawn Savery

Carles Gaston-Massuet

Gabriel L Galea

Nicholas D E Greene

Andrew J Copp

Affiliations

Soon will be listed here.

Abstract

Understanding the molecular mechanisms that lead to birth defects is an important step towards improved primary prevention. Mouse embryos homozygous for the Kumba (Ku) mutant allele of Zic2 develop severe spina bifida with complete lack of dorsolateral hinge points (DLHPs) in the neuroepithelium. Bone morphogenetic protein (BMP) signalling is overactivated in Zic2Ku/Ku embryos, and the BMP inhibitor dorsomorphin partially rescues neural tube closure in cultured embryos. RhoA signalling is also overactivated, with accumulation of actomyosin in the Zic2Ku/Ku neuroepithelium, and the myosin inhibitor Blebbistatin partially normalises neural tube closure. However, dorsomorphin and Blebbistatin differ in their effects at tissue and cellular levels: DLHP formation is rescued by dorsomorphin but not Blebbistatin, whereas abnormal accumulation of actomyosin is rescued by Blebbistatin but not dorsomorphin. These findings suggest a dual mechanism of spina bifida origin in Zic2Ku/Ku embryos: faulty BMP-dependent formation of DLHPs and RhoA-dependent F-actin accumulation in the neuroepithelium. Hence, we identify a multi-pathway origin of spina bifida in a mammalian system that may provide a developmental basis for understanding the corresponding multifactorial human defects.

Citing Articles

A computational dynamic systems model for prediction of neural tube closure defects.

Berkhout J, Glazier J, Piersma A, Belmonte J, Legler J, Spencer R Curr Res Toxicol. 2025; 8:100210.

PMID: 40034255 PMC: 11875186. DOI: 10.1016/j.crtox.2024.100210.

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