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ResearchIn-Press PreviewGastroenterologyGenetics Open Access | 10.1172/JCI198531

Vinculin influences essential processes in enteric nervous system development and Hirschsprung disease pathogenesis

Lifang Liu,1 Xixin Wang,1 Mingxuan Liang,2 Peiting Li,1 Cindy Yifei Yan,1 Patrick Ho-Yu Chung,1 Kenneth Kak-Yuen Wong,1 Asif Javed,2 Maria-Mercedes Garcia-Barcelo,1 and Elly Sau-Wai Ngan1

1Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

2School of Biomedical Science, The University of Hong Kong, Hong Kong, Hong Kong

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1Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

2School of Biomedical Science, The University of Hong Kong, Hong Kong, Hong Kong

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1Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

2School of Biomedical Science, The University of Hong Kong, Hong Kong, Hong Kong

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1Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

2School of Biomedical Science, The University of Hong Kong, Hong Kong, Hong Kong

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1Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

2School of Biomedical Science, The University of Hong Kong, Hong Kong, Hong Kong

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1Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

2School of Biomedical Science, The University of Hong Kong, Hong Kong, Hong Kong

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1Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

2School of Biomedical Science, The University of Hong Kong, Hong Kong, Hong Kong

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1Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

2School of Biomedical Science, The University of Hong Kong, Hong Kong, Hong Kong

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1Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

2School of Biomedical Science, The University of Hong Kong, Hong Kong, Hong Kong

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1Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

2School of Biomedical Science, The University of Hong Kong, Hong Kong, Hong Kong

Find articles by Ngan, E. in: PubMed | Google Scholar

Published December 9, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI198531.
Copyright © 2025, Liu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 9, 2025 - Version history
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Abstract

Vinculin (VCL), a linker between cells and their environment, has rarely been linked to disease. This study examines the role of VCL in the development of the enteric nervous system (ENS) and its relationship to Hirschsprung disease (HSCR). Using whole-genome sequencing and in vitro assays, we identified four VCL mutations associated with HSCR, most causing loss of function. Neural crest-specific Vcl knock-out mice (Vcl cKO) displayed ENS defects resembling short-segment HSCR, including partial colonic aganglionosis and abnormal gut musculature. Single-cell transcriptomics revealed dysregulation of genes involved in neuronal differentiation and MAPK signaling. Spatial RNA sequencing revealed reduced ENS-mesenchyme interactions in Vcl cKO mice, accompanied by significant disruption of the Pleiotrophin (PTN) pathway; Ptn knock-out mice exhibited phenotypes similar to those of Vcl cKO mice, underscoring the importance of ENS-mesenchyme crosstalk. VCL works as a hub gene crucial for cell connection and signaling pathways essential for ENS formation. VCL deficiency subtly impacts various developmental stages and neighboring cells, cumulatively leading to a phenotype similar to short-segment HSCR. This research highlights the role of VCL in maintaining cellular interactions and signaling pathways, such as MAPK and PTN, which are crucial for ENS development and may inform therapeutic targets for ENS disorders.  

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  • Version 1 (December 9, 2025): In-Press Preview
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