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A collagen VI–dependent pathogenic mechanism for Hirschsprung’s disease
Rodolphe Soret, … , Nicolas Pilon, for the Ente-Hirsch study group
Rodolphe Soret, … , Nicolas Pilon, for the Ente-Hirsch study group
Published November 16, 2015
Citation Information: J Clin Invest. 2015;125(12):4483-4496. https://doi.org/10.1172/JCI83178.
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Research Article Development Gastroenterology Article has an altmetric score of 6

A collagen VI–dependent pathogenic mechanism for Hirschsprung’s disease

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Abstract

Hirschsprung’s disease (HSCR) is a severe congenital anomaly of the enteric nervous system (ENS) characterized by functional intestinal obstruction due to a lack of intrinsic innervation in the distal bowel. Distal innervation deficiency results from incomplete colonization of the bowel by enteric neural crest cells (eNCCs), the ENS precursors. Here, we report the generation of a mouse model for HSCR — named Holstein — that contains an untargeted transgenic insertion upstream of the collagen-6α4 (Col6a4) gene. This insertion induces eNCC-specific upregulation of Col6a4 expression that increases total collagen VI protein levels in the extracellular matrix (ECM) surrounding both the developing and the postnatal ENS. Increased collagen VI levels during development mainly result in slower migration of eNCCs. This appears to be due to the fact that collagen VI is a poor substratum for supporting eNCC migration and can even interfere with the migration-promoting effects of fibronectin. Importantly, for a majority of patients in a HSCR cohort, the myenteric ganglia from the ganglionated region are also specifically surrounded by abundant collagen VI microfibrils, an outcome accentuated by Down syndrome. Collectively, our data thus unveil a clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM composition surrounding eNCCs. Moreover, as COL6A1 and COL6A2 are on human Chr.21q, this mechanism is highly relevant to the predisposition of patients with Down syndrome to HSCR.

Authors

Rodolphe Soret, Mathilde Mennetrey, Karl F. Bergeron, Anne Dariel, Michel Neunlist, Franziska Grunder, Christophe Faure, David W. Silversides, Nicolas Pilon, for the Ente-Hirsch study group

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Figure 5

Cell-autonomous defect in HolTg/Tg eNCC migration.

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Cell-autonomous defect in HolTg/Tg eNCC migration.
(A) Representative im...
(A) Representative images of heterotopic E12.5 midgut-hindgut grafts after 24 hours of culture, showing that colonization of WT host tissues (aneural hindgut segments) by RFP-labeled eNCCs is much less efficient with mutant (HolTg/Tg G4-RFP) than with control (WT G4-RFP) midgut segments as donor tissues. Red arrowheads point to the location of the migration front at the end of the culture period. Scale bar: 150 μm. (B) Quantitative analysis of the extent of hindgut colonization by eNCCs coming from midgut tissues (data are presented as mean ± SEM; n = 5 grafts per combination; *P < 0.001; Student’s t test). (C) Representative images from 10-hour-long time-lapse recordings of eNCC movement at the migration front in WT and HolTg/Tg E13.5 intestines. The white arrows indicate the direction of colonization, whereas blue and orange arrowheads point to the location of the migration front at the start and end of recordings, respectively. Scale bar: 100 μm. (D) Quantification of the speed of individual cells at the tip of the migration front shows that HolTg/Tg eNCCs are significantly slower than WT eNCCs at both the E12.5 and E13.5 stages (data are presented as mean ± SEM; n represents the total number of cells from at least 3 intestines; *P < 0.01; Student’s t test).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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