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Article: Identification of GLI Mutations in Patients with Hirschsprung Disease That Disrupt Enteric Nervous System Development in Mice

TitleIdentification of GLI Mutations in Patients with Hirschsprung Disease That Disrupt Enteric Nervous System Development in Mice
Authors
KeywordsAganglionic Megacolon
HSCR
Mouse Model
Nervous System Development
Issue Date2015
PublisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro
Citation
Gastroenterology, 2015, v. 149 n. 7, p. 1837-1848.e5 How to Cite?
AbstractBackground & Aims: Hirschsprung disease is characterized by a deficit in enteric neurons, which are derived from neural crest cells (NCCs). Aberrant hedgehog signaling disrupts NCC differentiation and might cause Hirschsprung disease. We performed genetic analyses to determine whether hedgehog signaling is involved in pathogenesis. Methods: We performed deep-target sequencing of DNA from 20 patients with Hirschsprung disease (16 men, 4 women), and 20 individuals without (controls), and searched for mutation(s) in GLI1, GLI2, GLI3, SUFU, and SOX10. Biological effects of GLI mutations were tested in luciferase reporter assays using HeLa or neuroblastoma cell lines. Development of the enteric nervous system was studied in Sufuf/f, Gli3Δ699, Wnt1-Cre, and Sox10NGFP mice using immunohistochemical and whole-mount staining procedures to quantify enteric neurons and glia and analyze axon fasciculation, respectively. NCC migration was studied using time-lapse imaging. Results: We identified 3 mutations in GLI in 5 patients with Hirschsprung disease but no controls; all lead to increased transcription of SOX10 in cell lines. SUFU, GLI, and SOX10 form a regulatory loop that controls the neuronal vs glial lineages and migration of NCCs. Sufu mutants mice had high Gli activity, due to loss of Sufu, disrupting the regulatory loop and migration of enteric NCCs, leading to defective axonal fasciculation, delayed gut colonization, or intestinal hypoganglionosis. The ratio of enteric neurons to glia correlated inversely with Gli activity. Conclusions: We identified mutations that increase GLI activity in patients with Hirschsprung disease. Disruption of the SUFU−GLI−SOX10 regulatory loop disrupts migration of NCCs and development of the enteric nervous system in mice.
Persistent Identifierhttp://hdl.handle.net/10722/214972
ISSN
2017 Impact Factor: 20.773
2015 SCImago Journal Rankings: 7.170
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, AJ-
dc.contributor.authorLai, FPL-
dc.contributor.authorGui, HS-
dc.contributor.authorSham, MH-
dc.contributor.authorTam, PKH-
dc.contributor.authorGarcia-Barcelo, MM-
dc.contributor.authorHui, CC-
dc.contributor.authorNgan, ESW-
dc.date.accessioned2015-08-21T12:15:22Z-
dc.date.available2015-08-21T12:15:22Z-
dc.date.issued2015-
dc.identifier.citationGastroenterology, 2015, v. 149 n. 7, p. 1837-1848.e5-
dc.identifier.issn0016-5085-
dc.identifier.urihttp://hdl.handle.net/10722/214972-
dc.description.abstractBackground & Aims: Hirschsprung disease is characterized by a deficit in enteric neurons, which are derived from neural crest cells (NCCs). Aberrant hedgehog signaling disrupts NCC differentiation and might cause Hirschsprung disease. We performed genetic analyses to determine whether hedgehog signaling is involved in pathogenesis. Methods: We performed deep-target sequencing of DNA from 20 patients with Hirschsprung disease (16 men, 4 women), and 20 individuals without (controls), and searched for mutation(s) in GLI1, GLI2, GLI3, SUFU, and SOX10. Biological effects of GLI mutations were tested in luciferase reporter assays using HeLa or neuroblastoma cell lines. Development of the enteric nervous system was studied in Sufuf/f, Gli3Δ699, Wnt1-Cre, and Sox10NGFP mice using immunohistochemical and whole-mount staining procedures to quantify enteric neurons and glia and analyze axon fasciculation, respectively. NCC migration was studied using time-lapse imaging. Results: We identified 3 mutations in GLI in 5 patients with Hirschsprung disease but no controls; all lead to increased transcription of SOX10 in cell lines. SUFU, GLI, and SOX10 form a regulatory loop that controls the neuronal vs glial lineages and migration of NCCs. Sufu mutants mice had high Gli activity, due to loss of Sufu, disrupting the regulatory loop and migration of enteric NCCs, leading to defective axonal fasciculation, delayed gut colonization, or intestinal hypoganglionosis. The ratio of enteric neurons to glia correlated inversely with Gli activity. Conclusions: We identified mutations that increase GLI activity in patients with Hirschsprung disease. Disruption of the SUFU−GLI−SOX10 regulatory loop disrupts migration of NCCs and development of the enteric nervous system in mice.-
dc.languageeng-
dc.publisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro-
dc.relation.ispartofGastroenterology-
dc.subjectAganglionic Megacolon-
dc.subjectHSCR-
dc.subjectMouse Model-
dc.subjectNervous System Development-
dc.titleIdentification of GLI Mutations in Patients with Hirschsprung Disease That Disrupt Enteric Nervous System Development in Mice-
dc.typeArticle-
dc.identifier.emailLiu, AJ: jessie11@hku.hk-
dc.identifier.emailLai, FPL: laifrank@hku.hk-
dc.identifier.emailGui, HS: kuei1985@hku.hk-
dc.identifier.emailSham, MH: mhsham@hku.hk-
dc.identifier.emailTam, PKH: paultam@hku.hk-
dc.identifier.emailGarcia-Barcelo, MM: mmgarcia@hkucc.hku.hk-
dc.identifier.emailNgan, ESW: engan@hku.hk-
dc.identifier.authorityLiu, AJ=rp02546-
dc.identifier.authoritySham, MH=rp00380-
dc.identifier.authorityTam, PKH=rp00060-
dc.identifier.authorityGarcia-Barcelo, MM=rp00445-
dc.identifier.authorityNgan, ESW=rp00422-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1053/j.gastro.2015.07.060-
dc.identifier.pmid26261006-
dc.identifier.scopuseid_2-s2.0-84952986428-
dc.identifier.hkuros248597-
dc.identifier.hkuros254908-
dc.identifier.volume149-
dc.identifier.issue7-
dc.identifier.spage1837-
dc.identifier.epage1848.e5-
dc.identifier.isiWOS:000365808100037-
dc.publisher.placeUnited States-

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