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Perturbation of hoxb5 signaling in vagal neural crests down-regulates ret leading to intestinal hypoganglionosis in mice.
- Source :
-
Gastroenterology [Gastroenterology] 2008 Apr; Vol. 134 (4), pp. 1104-15. Date of Electronic Publication: 2008 Jan 17. - Publication Year :
- 2008
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Abstract
- Background & Aims: The enteric nervous system (ENS) controls intestinal peristalsis, and defective development of this system results in hypo/aganglionosis, as seen in Hirschsprung's disease. In the embryo, vagal neural crest cells (NCC) migrate and colonize the intestine rostrocaudally then differentiate into the ganglia of the ENS. Vagal NCC express the homeobox gene Hoxb5, a transcriptional activator, in human and mouse, so we used transgenic mice to investigate the function of Hoxb5 and the receptor tyrosine kinase gene Ret, which is affected in many patients with Hirschsprung's disease, in ENS development.<br />Methods: We perturbed the Hoxb5 pathway by expressing a chimeric protein enb5, in which the transcription activation domain of Hoxb5 was replaced with the repressor domain of the Drosophila engrailed protein (en), in vagal NCC. This enb5 transcriptional repressor competes with wild-type Hoxb5 for binding to target genes, exerting a dominant negative effect.<br />Results: We observed that 30.6% +/- 2.3% of NCC expressed enb5 and that these enb5-expressing NCC failed to migrate to the distal intestine. A 34%-37% reduction of ganglia (hypoganglionosis) and slow peristalsis and, occasionally, absence of ganglia and intestinal obstruction were observed in enb5-expressing mice. Ret expression was markedly reduced or absent in NCC and ganglia, and enb5 blocked Hoxb5 induction of Ret in neuroblastoma cells.<br />Conclusions: Our data indicate that Ret is a downstream target of Hoxb5 whose perturbation causes Ret haploinsufficiency, impaired NCC migration, and hypo/aganglionosis, suggesting that Hoxb5 may contribute to the etiology of Hirschsprung's disease.
- Subjects :
- Animals
Disease Models, Animal
Enteric Nervous System abnormalities
Enteric Nervous System metabolism
Female
Gene Expression Regulation, Developmental
Hirschsprung Disease embryology
Hirschsprung Disease genetics
Hirschsprung Disease metabolism
Homeodomain Proteins biosynthesis
Intestines physiopathology
Male
Mice
Mice, Transgenic
Neural Crest abnormalities
Neural Crest embryology
Peristalsis physiology
Proto-Oncogene Proteins c-ret metabolism
Signal Transduction physiology
Vagus Nerve abnormalities
Vagus Nerve embryology
DNA genetics
Down-Regulation
Homeodomain Proteins genetics
Intestines innervation
Neural Crest metabolism
Proto-Oncogene Proteins c-ret genetics
Vagus Nerve metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 134
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 18395091
- Full Text :
- https://doi.org/10.1053/j.gastro.2008.01.028