Gfra1 Underexpression Causes Hirschsprung's Disease and Associated Enterocolitis in Mice

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Porokuokka , L L , Virtanen , H T , Linden , J , Sidorova , Y , Danilova , T , Lindahl , M , Saarma , M & Andressoo , J-O 2019 , ' Gfra1 Underexpression Causes Hirschsprung's Disease and Associated Enterocolitis in Mice ' , Cellular and Molecular Gastroenterology and Hepatology , vol. 7 , no. 3 , pp. 655-678 .

Title: Gfra1 Underexpression Causes Hirschsprung's Disease and Associated Enterocolitis in Mice
Author: Porokuokka, L. Lauriina; Virtanen, Heikki T.; Linden, Jere; Sidorova, Yulia; Danilova, Tatiana; Lindahl, Maria; Saarma, Mart; Andressoo, Jaan-Olle
Contributor organization: Department of Pharmacology
Institute of Biotechnology
Veterinary Pathology and Parasitology
Veterinary Biosciences
Faculty of Veterinary Medicine
Mart Saarma / Principal Investigator
University Management
Helsinki One Health (HOH)
Date: 2019
Language: eng
Number of pages: 24
Belongs to series: Cellular and Molecular Gastroenterology and Hepatology
ISSN: 2352-345X
Abstract: BACKGROUND & AIMS: RET, the receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands, is the most frequently mutated gene in congenital aganglionic megacolon or Hirschsprung's disease (HSCR). The leading cause of mortality in HSCR is HSCR-associated enterocolitis (HAEC), which is characterized by altered mucin composition, mucin retention, bacterial adhesion to enterocytes, and epithelial damage, although the order of these events is obscure. In mice, loss of GDNF signaling leads to a severely underdeveloped enteric nervous system and neonatally fatal kidney agenesis, thereby precluding the use of these mice for modeling postnatal HSCR and HAEC. Our aim was to generate a postnatally viable mouse model for HSCR/HAEC and analyze HAEC etiology. METHODS: GDNF family receptor alpha-1 (GFRa1) hypomorphic mice were generated by placing a selectable marker gene in the sixth intron of the Gfra1 locus using gene targeting in mouse embryonic stem cells. RESULTS: We report that 70%-80% reduction in GDNF co-receptor GFRa1 expression levels in mice results in HSCR and HAEC, leading to death within the first 25 postnatal days. These mice mirror the disease progression and histopathologic findings in children with untreated HSCR/HAEC. CONCLUSIONS: In GFRa1 hypomorphic mice, HAEC proceeds from goblet cell dysplasia, with abnormal mucin production and retention, to epithelial damage. Microbial enterocyte adherence and tissue invasion are late events and therefore unlikely to be the primary cause of HAEC. These results suggest that goblet cells may be a potential target for preventative treatment and that reduced expression of GFRa1 may contribute to HSCR susceptibility.
Subject: Aganglionosis
Transgenic Mouse Model
3111 Biomedicine
1184 Genetics, developmental biology, physiology
3112 Neurosciences
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: publishedVersion

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