神戸大学 · 医学研究科/医学部 · 助教

研究キーワードenteric nervous system development・RET signaling・Hirschsprung disease・neuronal migration・semaphorin guidance・neural crest cells

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• Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice2021 · Society for Neuroscience, 2021年05月, eneuro, 8(3) (3), ENEURO.0534 - 20.2021, 英語
• Retrograde transport of neurotrophic factor signaling: implications in neuronal development and pathogenesis2016 · Oxford University Press (OUP), 2016年08月, Journal of Biochemistry, 160(2) (2), 77 - 85, 英語
• GDNF and endothelin 3 regulate migration of enteric neural crest-derived cells via PKA and Rac12013 · 2013年, Journal of Neuroscience, 33(11) (11), 4901 - 4912, 英語
• A single RET mutation in Hirschsprung disease induces intestinal aganglionosis via a dominant-negative mechanismBACKGROUND & AIMS: Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of the enteric nervous system (ENS). HSCR potentially involves multiple gene aberrations and displays complex patterns of inheritance. Mutations of the RET gene, encoding the RET receptor tyrosine kinase, play a central role in the pathogenesis of HSCR. Although a wide variety of coding RET mutations have been identified, their pathogenetic significance in vivo has remained largely unclear. METHODS: We introduced a HSCR-associated RET missense mutation, RET(S811F), into the corresponding region (S812) of the mouse Ret gene. Pathogenetic impact of Ret(S812F) was assessed by histologic and functional analyses of the ENS and by biochemical analyses. Interactions of the Ret(S812F) allele with HSCR susceptibility genes, the RET9 allele and the Ednrb gene, were examined by genetic crossing in mice. RESULTS: RetS812F/+ mice displayed intestinal aganglionosis (incidence, 50%) or hypoganglionosis (50%), impaired differentiation of enteric neurons, defecation deficits, and increased lethality. Biochemical analyses revealed that Ret(S811F) protein was not only kinase-deficient but also abrogated function of wild-type RET in trans. Moreover, the Ret(S812F) allele interacted with other HSCR susceptibility genes and caused intestinal aganglionosis with full penetrance. CONCLUSIONS: This study demonstrates that a single RET missense mutation alone induces intestinal aganglionosis via a dominant-negative mechanism. The RetS812F/+ mice model HSCR displays dominant inheritance with incomplete penetrance and serves as a valuable platform for better understanding of the pathogenetic mechanism of HSCR caused by coding RET mutations.

• 臓性知覚神経回路の真に特異的な標識・人為操作による腸脳連関地図の解明 伊藤圭祐 科学技術振興機構, CREST多細胞領域 YORCプログラム 2024（継続課題）, 2024年04月 - 2025年03月, 研究代表者2024 · KUID parsed section
• 臓性知覚神経回路の真に特異的な標識・人為操作による腸脳連関地図の解明 伊藤圭祐 科学技術振興機構, CREST多細胞領域 YORCプログラム 2023（継続課題）, 2023年04月 - 2024年03月, 研究代表者2023 · KUID parsed section
• 臓性知覚神経回路の真に特異的な標識・人為操作による腸脳連関地図の解明 伊藤圭祐 科学技術振興機構, CREST多細胞領域 YORCプログラム 2022（新規課題）, 2022年04月 - 2023年03月, 研究代表者2022 · KUID parsed section
• 前肢に存在する「神経様細胞」の異常産生と、神経芽腫発症の共通分子基盤を探る 伊藤 圭祐 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2022年04月 - 2025年03月, 研究代表者2022 · KUID parsed section

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