Escuin, Sarah;
Raza-Knight, Saba Rose;
Savery, Dawn;
Gaston-Massuet, Carles;
Galea, Gabriel L;
Greene, Nicholas DE;
Copp, Andrew J;
(2023)
Dual mechanism underlying failure of neural tube closure in the Zic2 mutant mouse.
Disease Models and Mechanisms
, 16
(3)
, Article dmm049858. 10.1242/dmm.049858.
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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 over-activated in Zic2Ku/Ku embryos, and the BMP inhibitor dorsomorphin partially rescues neural tube closure in cultured embryos. RhoA signalling is also over-activated, 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: BMP-dependent formation of DLHPs is faulty, together with 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.
| Type: | Article |
|---|---|
| Title: | Dual mechanism underlying failure of neural tube closure in the Zic2 mutant mouse |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1242/dmm.049858 |
| Publisher version: | https://doi.org/10.1242/dmm.049858 |
| Language: | English |
| Additional information: | Copyright © 2023. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
| Keywords: | Actomyosin, BMP, Embryo, Morphogenesis, Neural tube defects, Neurulation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10166319 |
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