Article: Perturbation of Hoxb5 Signaling in Vagal Neural Crests Down-Regulates Ret Leading to Intestinal Hypoganglionosis in Mice

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TitlePerturbation of Hoxb5 Signaling in Vagal Neural Crests Down-Regulates Ret Leading to Intestinal Hypoganglionosis in Mice
AuthorsLui, VCH2
Cheng, WWC2
Leon, TYY2
Lau, DKC2
GarciaBareclo, M2
Miao, XP2
Kam, MKM2
So, MT2
Chen, Y2
Wall, NA1
Sham, MH2
Tam, PKH2
Issue Date2008
PublisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro
CitationGastroenterology, 2008, v. 134 n. 4, p. 1104-1115 [How to Cite?]
DOI: http://dx.doi.org/10.1053/j.gastro.2008.01.028
AbstractBackground & 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. 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. 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. 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. © 2008 AGA Institute.
ISSN0016-5085
2011 Impact Factor: 11.675
2011 SCImago Journal Rankings: 1.055
DOIhttp://dx.doi.org/10.1053/j.gastro.2008.01.028
ISI Accession Number IDWOS:000254853800030
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorLui, VCH
dc.contributor.authorCheng, WWC
dc.contributor.authorLeon, TYY
dc.contributor.authorLau, DKC
dc.contributor.authorGarciaBareclo, M
dc.contributor.authorMiao, XP
dc.contributor.authorKam, MKM
dc.contributor.authorSo, MT
dc.contributor.authorChen, Y
dc.contributor.authorWall, NA
dc.contributor.authorSham, MH
dc.contributor.authorTam, PKH
dc.date.accessioned2010-09-06T06:03:03Z
dc.date.available2010-09-06T06:03:03Z
dc.date.issued2008
dc.description.abstractBackground & 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. 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. 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. 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. © 2008 AGA Institute.
dc.description.naturelink_to_subscribed_fulltext
dc.identifier.citationGastroenterology, 2008, v. 134 n. 4, p. 1104-1115 [How to Cite?]
DOI: http://dx.doi.org/10.1053/j.gastro.2008.01.028
dc.identifier.doihttp://dx.doi.org/10.1053/j.gastro.2008.01.028
dc.identifier.epage1115
dc.identifier.hkuros141326
dc.identifier.isiWOS:000254853800030
dc.identifier.issn0016-5085
2011 Impact Factor: 11.675
2011 SCImago Journal Rankings: 1.055
dc.identifier.issue4
dc.identifier.openurl
dc.identifier.pmid18395091
dc.identifier.scopuseid_2-s2.0-41349099140
dc.identifier.spage1104
dc.identifier.urihttp://hdl.handle.net/10722/68277
dc.identifier.volume134
dc.languageeng
dc.publisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro
dc.publisher.placeUnited States
dc.relation.ispartofGastroenterology
dc.relation.referencesReferences in Scopus
dc.subject.meshAnimals
dc.subject.meshDNA - genetics
dc.subject.meshDisease Models, Animal
dc.subject.meshDown-Regulation
dc.subject.meshEnteric Nervous System - abnormalities - metabolism
dc.subject.meshFemale
dc.subject.meshGene Expression Regulation, Developmental
dc.subject.meshHirschsprung Disease - embryology - genetics - metabolism
dc.subject.meshHomeodomain Proteins - biosynthesis - genetics
dc.subject.meshIntestines - innervation - physiopathology
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshMice, Transgenic
dc.subject.meshNeural Crest - abnormalities - embryology - metabolism
dc.subject.meshPeristalsis - physiology
dc.subject.meshProto-Oncogene Proteins c-ret - genetics - metabolism
dc.subject.meshSignal Transduction - physiology
dc.subject.meshVagus Nerve - abnormalities - embryology - metabolism
dc.titlePerturbation of Hoxb5 Signaling in Vagal Neural Crests Down-Regulates Ret Leading to Intestinal Hypoganglionosis in Mice
dc.typeArticle
Author Affiliations
  1. Lawrence University, Appleton
  2. The University of Hong Kong Li Ka Shing Faculty of Medicine