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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, VCH1
Cheng, WWC1
Leon, TYY1
Lau, DKC1
GarciaBareclo, M1
Miao, XP1
Kam, MKM1
So, MT1
Chen, Y1
Wall, NA2
Sham, MH1
Tam, PKH1
 
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
2012 Impact Factor: 12.821
2012 SCImago Journal Rankings: 3.649
 
DOIhttp://dx.doi.org/10.1053/j.gastro.2008.01.028
 
ISI Accession Number IDWOS:000254853800030
 
ReferencesReferences in Scopus
 
DC FieldValue
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.eissn1528-0012
 
dc.identifier.epage1115
 
dc.identifier.hkuros141326
 
dc.identifier.isiWOS:000254853800030
 
dc.identifier.issn0016-5085
2012 Impact Factor: 12.821
2012 SCImago Journal Rankings: 3.649
 
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
 
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<contributor.author>Cheng, WWC</contributor.author>
<contributor.author>Leon, TYY</contributor.author>
<contributor.author>Lau, DKC</contributor.author>
<contributor.author>GarciaBareclo, M</contributor.author>
<contributor.author>Miao, XP</contributor.author>
<contributor.author>Kam, MKM</contributor.author>
<contributor.author>So, MT</contributor.author>
<contributor.author>Chen, Y</contributor.author>
<contributor.author>Wall, NA</contributor.author>
<contributor.author>Sham, MH</contributor.author>
<contributor.author>Tam, PKH</contributor.author>
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<description.abstract>Background &amp; Aims: The enteric nervous system (ENS) controls intestinal peristalsis, and defective development of this system results in hypo/aganglionosis, as seen in Hirschsprung&apos;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&apos;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% &#177; 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&apos;s disease. &#169; 2008 AGA Institute.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Lawrence University, Appleton