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Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice

Mutations of the gene encoding the RET tyrosine kinase causes Hirschsprung’s disease (HSCR) and medullary thyroid carcinoma (MTC). Current consensus holds that HSCR and MTC are induced by inactivating and activating RET mutations, respectively. However, it remains unknown whether activating mutation...

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Autores principales: Okamoto, Mitsumasa, Uesaka, Toshihiro, Ito, Keisuke, Enomoto, Hideki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174796/
https://www.ncbi.nlm.nih.gov/pubmed/33958373
http://dx.doi.org/10.1523/ENEURO.0534-20.2021
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author Okamoto, Mitsumasa
Uesaka, Toshihiro
Ito, Keisuke
Enomoto, Hideki
author_facet Okamoto, Mitsumasa
Uesaka, Toshihiro
Ito, Keisuke
Enomoto, Hideki
author_sort Okamoto, Mitsumasa
collection PubMed
description Mutations of the gene encoding the RET tyrosine kinase causes Hirschsprung’s disease (HSCR) and medullary thyroid carcinoma (MTC). Current consensus holds that HSCR and MTC are induced by inactivating and activating RET mutations, respectively. However, it remains unknown whether activating mutations in the RET gene have adverse effects on ENS development in vivo. We addressed this issue by examining mice engineered to express RET51(C618F), an activating mutation identified in MTC patients. Although Ret(51(C618F)/51(C618F))mice displayed hyperganglionosis of the ENS, Ret(51(C618F)/-) mice exhibited severe intestinal aganglionosis because of premature neuronal differentiation. Reduced levels of glial cell-derived neurotrophic factor (GDNF), a RET-activating neurotrophic factor, ameliorated the ENS phenotype of Ret(51(C618F)/-) mice, demonstrating that GDNF-mediated activation of RET51(C618F) is responsible for severe aganglionic phenotype. The RET51(C618F) allele showed genetic interaction with Ednrb gene, one of modifier genes for HSCR. These data reveal that proliferation and differentiation of ENS precursors are exquisitely controlled by both the activation levels and total dose of RET. Increased RET activity coupled with a decreased gene dosage can cause intestinal aganglionosis, a finding that provides novel insight into HSCR pathogenesis.
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spelling pubmed-81747962021-06-04 Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice Okamoto, Mitsumasa Uesaka, Toshihiro Ito, Keisuke Enomoto, Hideki eNeuro Research Article: New Research Mutations of the gene encoding the RET tyrosine kinase causes Hirschsprung’s disease (HSCR) and medullary thyroid carcinoma (MTC). Current consensus holds that HSCR and MTC are induced by inactivating and activating RET mutations, respectively. However, it remains unknown whether activating mutations in the RET gene have adverse effects on ENS development in vivo. We addressed this issue by examining mice engineered to express RET51(C618F), an activating mutation identified in MTC patients. Although Ret(51(C618F)/51(C618F))mice displayed hyperganglionosis of the ENS, Ret(51(C618F)/-) mice exhibited severe intestinal aganglionosis because of premature neuronal differentiation. Reduced levels of glial cell-derived neurotrophic factor (GDNF), a RET-activating neurotrophic factor, ameliorated the ENS phenotype of Ret(51(C618F)/-) mice, demonstrating that GDNF-mediated activation of RET51(C618F) is responsible for severe aganglionic phenotype. The RET51(C618F) allele showed genetic interaction with Ednrb gene, one of modifier genes for HSCR. These data reveal that proliferation and differentiation of ENS precursors are exquisitely controlled by both the activation levels and total dose of RET. Increased RET activity coupled with a decreased gene dosage can cause intestinal aganglionosis, a finding that provides novel insight into HSCR pathogenesis. Society for Neuroscience 2021-05-28 /pmc/articles/PMC8174796/ /pubmed/33958373 http://dx.doi.org/10.1523/ENEURO.0534-20.2021 Text en Copyright © 2021 Okamoto et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article: New Research
Okamoto, Mitsumasa
Uesaka, Toshihiro
Ito, Keisuke
Enomoto, Hideki
Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice
title Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice
title_full Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice
title_fullStr Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice
title_full_unstemmed Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice
title_short Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice
title_sort increased ret activity coupled with a reduction in the ret gene dosage causes intestinal aganglionosis in mice
topic Research Article: New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174796/
https://www.ncbi.nlm.nih.gov/pubmed/33958373
http://dx.doi.org/10.1523/ENEURO.0534-20.2021
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