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postgraduate thesis: Genetic interaction between Patched1 and Sox10 in enteric nervous system development

TitleGenetic interaction between Patched1 and Sox10 in enteric nervous system development
Authors
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Tam, C. [譚俊逸]. (2014). Genetic interaction between Patched1 and Sox10 in enteric nervous system development. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5481876
AbstractThe enteric nervous system (ENS) is derived from neural crest cells (NCCs). Once these NCCs reach the foregut, they are recognized as enteric NCCs(ENCCs) which subsequently colonize the gastrointestinal track. The proliferation, migration and neuronal versusglial differentiation of ENCCs are tightly controlled by multiple signaling pathways and transcription factors. Impaired ENS development may result in various human congenital disorders such as Hirschsprung disease(HSCR). Hedgehog (Hh) signaling is a key element in ENS development. Patched-1 (Ptch1) is a negatively regulated receptor for Hh. Binding to Hh or deletion of Ptch1releases its inhibitory function and activates the Hh signaling cascade. Our group has previously revealedPTCH1as a susceptibility gene for HSCR. In particular, NCC-specific deletionofPtch1in mice led to premature glial differentiation and depletion of proliferative ENCC pool, but the molecular mechanisms are still not very clear. Sox10, a member of SRY-related HMG-box family transcription factor, is implicated in these two processes of ENS development. It prompted us to hypothesis that Ptch1 may interact with Sox10 to control ENCC proliferation and glial lineage differentiation. In this study, I generated compound mouse mutants to i) investigate the potential functional interaction between Ptch1 and Sox10 in ENCC differentiation and proliferation, and ii) examine the link between the perturbed NCC differentiation and aberrant proliferation of ENS progenitors, to determine how interruption of these processes may lead to intestinal hypoganglionosis of Ptch1mutants. I found that persistent Hh activation through deletionofPtch1causes a differentiation bias toward glial lineage. Ptch1mutants consistently contained more Sox10expressing glial committed ENCCs and exhibited premature gliogenesis. To test whether elevated Sox10expressing cells contribute in the ENS phenotypes of Ptch1 mutants, 〖Sox10〗^(NGFP/+); Ptch1 compound mutants were generated, where one copy of Sox10 was deleted. Immunohistochemical analysis revealed that 〖Sox10〗^(NGFP/+) mutants exhibitpremature neurogenesis as reported previously, while the proliferation and glial differentiation of ENCCs are not affected.On the other hand, in the compound mutants, heterozygous deletion of Sox10 markedly rescued premature gliogenesis caused by deletion of Ptch1. These data suggest that Ptch1 regulates gliogenesis of ENCCs through maintaining Sox10 expression. To delineate how premature glial differentiation of ENCCs leads to hypoganglionosis, I further investigated whether the differentiation defect perturbs the proliferation capacities of ENCCs. Correction of glial differentiation defect in Ptch1 mutant by heterogeneous deletion of Sox10 could significantly restore the pool size of the proliferative ENCCs of the compound mutant. This observation implies that proliferation defects in Ptch1 mutant represents a secondary consequence of premature gliogenesis, highlighting the close link between these two developmental processes. In summary, the current study provides evidence that Sox10 works coordinately with Ptch1 to mediate ENS development. Loss of Ptch1 favors glial differentiation and formation ofSox10 expressing glial progenitors, leading to intestinal hypoganglionosis as seen in Hirschsprung’s disease.
DegreeMaster of Philosophy
SubjectCellular signal transduction
Transcription factors
Autonomic nervous system
Neurogenetics
Dept/ProgramSurgery
Persistent Identifierhttp://hdl.handle.net/10722/211149

 

DC FieldValueLanguage
dc.contributor.authorTam, Chun-yat-
dc.contributor.author譚俊逸-
dc.date.accessioned2015-07-07T23:10:48Z-
dc.date.available2015-07-07T23:10:48Z-
dc.date.issued2014-
dc.identifier.citationTam, C. [譚俊逸]. (2014). Genetic interaction between Patched1 and Sox10 in enteric nervous system development. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5481876-
dc.identifier.urihttp://hdl.handle.net/10722/211149-
dc.description.abstractThe enteric nervous system (ENS) is derived from neural crest cells (NCCs). Once these NCCs reach the foregut, they are recognized as enteric NCCs(ENCCs) which subsequently colonize the gastrointestinal track. The proliferation, migration and neuronal versusglial differentiation of ENCCs are tightly controlled by multiple signaling pathways and transcription factors. Impaired ENS development may result in various human congenital disorders such as Hirschsprung disease(HSCR). Hedgehog (Hh) signaling is a key element in ENS development. Patched-1 (Ptch1) is a negatively regulated receptor for Hh. Binding to Hh or deletion of Ptch1releases its inhibitory function and activates the Hh signaling cascade. Our group has previously revealedPTCH1as a susceptibility gene for HSCR. In particular, NCC-specific deletionofPtch1in mice led to premature glial differentiation and depletion of proliferative ENCC pool, but the molecular mechanisms are still not very clear. Sox10, a member of SRY-related HMG-box family transcription factor, is implicated in these two processes of ENS development. It prompted us to hypothesis that Ptch1 may interact with Sox10 to control ENCC proliferation and glial lineage differentiation. In this study, I generated compound mouse mutants to i) investigate the potential functional interaction between Ptch1 and Sox10 in ENCC differentiation and proliferation, and ii) examine the link between the perturbed NCC differentiation and aberrant proliferation of ENS progenitors, to determine how interruption of these processes may lead to intestinal hypoganglionosis of Ptch1mutants. I found that persistent Hh activation through deletionofPtch1causes a differentiation bias toward glial lineage. Ptch1mutants consistently contained more Sox10expressing glial committed ENCCs and exhibited premature gliogenesis. To test whether elevated Sox10expressing cells contribute in the ENS phenotypes of Ptch1 mutants, 〖Sox10〗^(NGFP/+); Ptch1 compound mutants were generated, where one copy of Sox10 was deleted. Immunohistochemical analysis revealed that 〖Sox10〗^(NGFP/+) mutants exhibitpremature neurogenesis as reported previously, while the proliferation and glial differentiation of ENCCs are not affected.On the other hand, in the compound mutants, heterozygous deletion of Sox10 markedly rescued premature gliogenesis caused by deletion of Ptch1. These data suggest that Ptch1 regulates gliogenesis of ENCCs through maintaining Sox10 expression. To delineate how premature glial differentiation of ENCCs leads to hypoganglionosis, I further investigated whether the differentiation defect perturbs the proliferation capacities of ENCCs. Correction of glial differentiation defect in Ptch1 mutant by heterogeneous deletion of Sox10 could significantly restore the pool size of the proliferative ENCCs of the compound mutant. This observation implies that proliferation defects in Ptch1 mutant represents a secondary consequence of premature gliogenesis, highlighting the close link between these two developmental processes. In summary, the current study provides evidence that Sox10 works coordinately with Ptch1 to mediate ENS development. Loss of Ptch1 favors glial differentiation and formation ofSox10 expressing glial progenitors, leading to intestinal hypoganglionosis as seen in Hirschsprung’s disease.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshCellular signal transduction-
dc.subject.lcshTranscription factors-
dc.subject.lcshAutonomic nervous system-
dc.subject.lcshNeurogenetics-
dc.titleGenetic interaction between Patched1 and Sox10 in enteric nervous system development-
dc.typePG_Thesis-
dc.identifier.hkulb5481876-
dc.description.thesisnameMaster of Philosophy-
dc.description.thesislevelMaster-
dc.description.thesisdisciplineSurgery-
dc.description.naturepublished_or_final_version-

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