Back to Search Start Over

A collagen VI-dependent pathogenic mechanism for Hirschsprung's disease

Authors :
Soret, Rodolphe
Mennetrey, Mathilde
Bergeron, Karl F.
Dariel, Anne
Neunlist, Michel
Grunder, Franziska
Faure, Christophe
Silversides, David W.
Pilon, Nicolas
Source :
Journal of Clinical Investigation. December 1, 2015, p4483, 14 p.
Publication Year :
2015

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 (Col6α4) 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.<br />Introduction The enteric nervous system (ENS) is located within the gut wall and is mainly composed of multiple interconnected ganglia organized into two main plexuses: the submucosal plexus and the [...]

Details

Language :
English
ISSN :
00219738
Database :
Gale General OneFile
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsgcl.436234507
Full Text :
https://doi.org/10.1172/JCI83178