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

TitlePerturbation of Hoxb5 Signaling in Vagal Neural Crests Down-Regulates Ret Leading to Intestinal Hypoganglionosis in Mice
Authors
Issue Date2008
PublisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro
Citation
Gastroenterology, 2008, v. 134 n. 4, p. 1104-1115 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/68277
ISSN
2014 Impact Factor: 16.716
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLui, VCHen_HK
dc.contributor.authorCheng, WWCen_HK
dc.contributor.authorLeon, TYYen_HK
dc.contributor.authorLau, DKCen_HK
dc.contributor.authorGarciaBareclo, Men_HK
dc.contributor.authorMiao, XPen_HK
dc.contributor.authorKam, MKMen_HK
dc.contributor.authorSo, MTen_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorWall, NAen_HK
dc.contributor.authorSham, MHen_HK
dc.contributor.authorTam, PKHen_HK
dc.date.accessioned2010-09-06T06:03:03Z-
dc.date.available2010-09-06T06:03:03Z-
dc.date.issued2008en_HK
dc.identifier.citationGastroenterology, 2008, v. 134 n. 4, p. 1104-1115en_HK
dc.identifier.issn0016-5085en_HK
dc.identifier.urihttp://hdl.handle.net/10722/68277-
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.en_HK
dc.languageengen_HK
dc.publisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastroen_HK
dc.relation.ispartofGastroenterologyen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshDNA - geneticsen_HK
dc.subject.meshDisease Models, Animalen_HK
dc.subject.meshDown-Regulationen_HK
dc.subject.meshEnteric Nervous System - abnormalities - metabolismen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshGene Expression Regulation, Developmentalen_HK
dc.subject.meshHirschsprung Disease - embryology - genetics - metabolismen_HK
dc.subject.meshHomeodomain Proteins - biosynthesis - geneticsen_HK
dc.subject.meshIntestines - innervation - physiopathologyen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Transgenicen_HK
dc.subject.meshNeural Crest - abnormalities - embryology - metabolismen_HK
dc.subject.meshPeristalsis - physiologyen_HK
dc.subject.meshProto-Oncogene Proteins c-ret - genetics - metabolismen_HK
dc.subject.meshSignal Transduction - physiologyen_HK
dc.subject.meshVagus Nerve - abnormalities - embryology - metabolismen_HK
dc.titlePerturbation of Hoxb5 Signaling in Vagal Neural Crests Down-Regulates Ret Leading to Intestinal Hypoganglionosis in Miceen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0016-5085&volume=134&issue=4&spage=1104&epage=1115&date=2008&atitle=Perturbation+of+Hoxb5+signaling+in+vagal+neural+crests+down-regulates+ret+leading+to+intestinal+hypoganglionosis+in+mice.en_HK
dc.identifier.emailLui, VCH: vchlui@hkucc.hku.hken_HK
dc.identifier.emailChen, Y: ychenc@hkucc.hku.hken_HK
dc.identifier.emailSham, MH: mhsham@hkucc.hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hkucc.hku.hken_HK
dc.identifier.authorityLui, VCH=rp00363en_HK
dc.identifier.authorityChen, Y=rp01318en_HK
dc.identifier.authoritySham, MH=rp00380en_HK
dc.identifier.authorityTam, PKH=rp00060en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1053/j.gastro.2008.01.028en_HK
dc.identifier.pmid18395091en_HK
dc.identifier.scopuseid_2-s2.0-41349099140en_HK
dc.identifier.hkuros141326en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-41349099140&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume134en_HK
dc.identifier.issue4en_HK
dc.identifier.spage1104en_HK
dc.identifier.epage1115en_HK
dc.identifier.eissn1528-0012-
dc.identifier.isiWOS:000254853800030-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLui, VCH=7004231344en_HK
dc.identifier.scopusauthoridCheng, WWC=35083207300en_HK
dc.identifier.scopusauthoridLeon, TYY=10641704600en_HK
dc.identifier.scopusauthoridLau, DKC=10642145100en_HK
dc.identifier.scopusauthoridGarciaBareclo, M=23987771900en_HK
dc.identifier.scopusauthoridMiao, XP=7102585391en_HK
dc.identifier.scopusauthoridKam, MKM=36719044000en_HK
dc.identifier.scopusauthoridSo, MT=8748542200en_HK
dc.identifier.scopusauthoridChen, Y=36463185300en_HK
dc.identifier.scopusauthoridWall, NA=7003411553en_HK
dc.identifier.scopusauthoridSham, MH=7003729109en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK

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