Genetically engineered ESC-derived embryos reveal Vinculin-dependent force responses required for mammalian neural tube closure

Sep 29, 2026

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Epithelial sheets generate complex structures by channeling converging mechanical forces into coordinated changes in cell and tissue organization. During mouse cranial neural tube closure, mechanical forces increase and recruit the force-sensitive protein Vinculin to adherens junctions. Using a genetically engineered embryonic stem cell-based pipeline to produce mutant embryos, the study shows Vinculin mutants generate appropriate forces but cannot maintain cell adhesion under tension, impairing cranial neural fold elevation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages56

Reading Time2 h 21 min

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Abstract

Introduction

bioRxiv preprint doi: [https://doi.org/10.64898/2025.12.22.696028](https://doi.org/10.64898/2025.12.22.696028); this version posted December 25, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Gene$cally engineered ESC-derived embryos reveal Vinculin-dependent force responses required for mammalian neural tube closure Ian S. Prudhomme1, Eric R. Brooks1,2, Nilay Taneja1, Bhaswa= Bha>acharya1, Brian J. LaFleche1, Yasuhide Furuta3, and Jennifer A. Zallen1,* 1 HHMI and Developmental Biology Program, Sloan Ke>ering Ins=tute 2 Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University 3 Mouse Gene=cs Core Facility, Sloan Ke>ering Ins=tute *For correspondence: [zallenj@mskcc.org](zallenj@mskcc.org) Abstract Epithelial sheets build complex structures by conver6ng mechanical forces into changes in cell and 6ssue organiza6on. During neural tube closure, the neural plate dynamically remodels to produce a closed tube that provides the structural founda6on for the developing brain and spinal cord. How cells maintain epithelial integrity despite the forces required for 6ssue morphogenesis during neural tube closure is not understood. We show that mechanical forces are upregulated during cranial neural tube closure in the mouse embryo and recruit the force-sensi6ve protein Vinculin to adherens junc6ons. Leveraging agene6cally engineered embryonic stem cell-based pipeline to eﬃciently generate mutant embryos, we show that Vinculin mutants produce mechanical forces correctly but fail to maintain cell adhesion under tension, resul6ng in a failure of cranial neural fold eleva6on. Live imaging of cell behavior in the developing midbrain reveals that apical constric6on, cell rearrangement, and cell division ini6ate correctly in Vinculin mutants, but their progression is impeded by disrup6on of adherens junc6ons at sites of increased tension. These results demonstrate that Vinculin is required to reinforce cell adhesion in response to increasing physiological forces during cranial neural tube closure, and that this ac6vity is necessary to translate these forces into changes in 6ssue structure. Introduc.on The development of mul6cellular organisms requires the genera6on of complex three-dimensional structures from simple sheets of cells. Forma6on of the mammalian brain involves dynamic changes in cell shape and organiza6on that transform an epithelial sheet into the closed neural tube that is essen6al for the development of the brain and spinal cord (Wilde et al., 2014; Juriloﬀ and Harris, 2018) . Disrup6ons in neural tube closure are among the most common causes of birth defects, aﬀec6 ng around 1 in 2,000 births, represen6ng a signiﬁcant challenge in human health (Wallingford et al., 2013; Zaganjor et al., 2016) . bioRxiv preprint doi: [https://doi.org/10.64898/2025.12.22.696028](https://doi.org/10.64898/2025.12.22.696028); this version posted December 25, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Neural tube closure requires the integra6on of mul6ple cell behaviors, including apical constric6on, cell division, and cell rearrangements, which promote epithelial reorganiza6on, bending, and fusion (Nikolopoulou et al., 2017; Vijayraghavan and Davidson, 2017; Matsuda and Sokol, 2021) . These processes are driven by spa6otemporally regulated actomyosin networks that are predicted to alter the physical environment experienced by individual cells and create mechanical stresses that could disrupt cell adhesion and epithelial integrity. However, the mechanical forces that drive mammalian n

FAQs

What role does Vinculin play during mouse cranial neural tube closure?

Mechanical forces upregulate during cranial neural tube closure and recruit Vinculin to adherens junctions, where it helps maintain epithelial integrity under increasing tension.

What happens to mechanical force levels and cell adhesion in Vinculin mutant embryos?

Vinculin mutants generate mechanical forces correctly but fail to maintain cell adhesion under tension, leading to defective cranial neural fold elevation.

Which cellular processes are affected in Vinculin mutants during neural tube closure?

Apical constriction, cell rearrangement, and cell division initiate correctly, but progression is impeded due to disruption of adherens junctions at sites experiencing increased tension.

Sep 29, 2026

Upload by SANS