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 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 Ret51(C618F)/51(C618F) mice displayed hyperganglionosis of the ENS, Ret51(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 Ret51(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.
Pubmed ID: 33958373 RIS Download
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- Donkey Anti-Goat IgG(H+L) Antibody, CF640R Conjugated (RRID:AB_10853145)
- Donkey Anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Antibody, CF568 Conjugated (RRID:AB_10557118)
- Donkey Anti-Goat IgG (H+L) Highly Cross-Adsorbed Antibody, CF568 Conjugated (RRID:AB_10559672)
- Donkey Anti-Chicken IgY (IgG) (H+L) Antibody, CF488A Conjugated (RRID:AB_10854387)
- Donkey Anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Antibody, CF488A Conjugated (RRID:AB_10559669)
- Anti-Green Fluorescent Protein Antibody (RRID:AB_10000240)
- p44/42 MAP kinase (phosphorylated Erk1/2) (RRID:AB_331646)
- PGP9.5 (protein gene product 9.5) (RRID:AB_2313685)
- Sox-10 (N-20) (RRID:AB_2195374)
- Phox2b (RRID:AB_2313690)
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Donkey Anti-Goat IgG(H+L) Antibody, CF640R Conjugated (antibody)
RRID:AB_10853145
This unknown targets Donkey Goat IgG(H+L) CF640R
View all literature mentionsDonkey Anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Antibody, CF568 Conjugated (antibody)
RRID:AB_10557118
This unknown targets Donkey Rabbit IgG (H+L) Highly Cross-Adsorbed CF568
View all literature mentionsDonkey Anti-Goat IgG (H+L) Highly Cross-Adsorbed Antibody, CF568 Conjugated (antibody)
RRID:AB_10559672
This unknown targets Donkey Goat IgG (H+L) Highly Cross-Adsorbed CF568
View all literature mentionsDonkey Anti-Chicken IgY (IgG) (H+L) Antibody, CF488A Conjugated (antibody)
RRID:AB_10854387
This unknown targets Donkey Chicken IgY (IgG) (H+L) CF488A
View all literature mentionsDonkey Anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Antibody, CF488A Conjugated (antibody)
RRID:AB_10559669
This unknown targets Donkey Rabbit IgG (H+L) Highly Cross-Adsorbed CF488A
View all literature mentionsAnti-Green Fluorescent Protein Antibody (antibody)
RRID:AB_10000240
This polyclonal targets Green Fluorescent Protein (GFP)
View all literature mentionsp44/42 MAP kinase (phosphorylated Erk1/2) (antibody)
RRID:AB_331646
This polyclonal targets Erk1/2
View all literature mentionsPGP9.5 (protein gene product 9.5) (antibody)
RRID:AB_2313685
This unknown targets
View all literature mentionsSox-10 (N-20) (antibody)
RRID:AB_2195374
This unknown targets Raised against peptide mapping to N-terminus of sox-10 of human origin
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