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A Quantitative Cell Migration Assay for Murine Enteric Neural Progenitors
Published on: September 18, 2013
The Ret(C620R) mutation affects renal and enteric development in a mouse model of Hirschsprung's disease
Cristiana Carniti1, Sara Belluco, Elena Riccardi
1Department of Experimental Oncology and Laboratories, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via G. Venezian 1, 20133 Milan, Italy. cristiana.carniti@istitutotumori.mi.it
Abstract:
In rare families RET tyrosine kinase receptor substitutions located in exon 10 (especially at positions 609, 618, and 620) can concomitantly cause the MEN 2A (multiple endocrine neoplasia type 2A) or FMTC (familial medullary thyroid carcinoma) cancer syndromes, and Hirschsprung's disease (HSCR). No animal model mimicking the co-existence of the MEN 2 pathology and HSCR is available, and the association of these activating mutations with a developmental defect still represents an unresolved problem. The aim of this work was to investigate the significance of the RET(C620R) substitution in the pathogenesis of both gain- and loss-of-function RET-associated diseases. We report the generation of a line of mice carrying the C620R mutation in the Ret gene. Although Ret(C620R) homozygotes display severe defects in kidney organogenesis and enteric nervous system development leading to perinatal lethality. Ret(C620R) heterozygotes recapitulate features characteristic of HSCR including hypoganglionosis of the gastrointestinal tract. Surprisingly, heterozygotes do not show any defects in the thyroid that might be attributable to a gain-of-function mutation. The Ret(C620R) allele is responsible for HSCR and affects the development of kidneys and the enteric nervous system (ENS). These mice represent an interesting model for studying new therapeutic approaches for the treatment of HSCR disease.
Insights
The RET(C620R) mutation causes Hirschsprung's disease (HSCR) and affects kidney and enteric nervous system development in mice. This new mouse model aids research into HSCR treatments.
Area of Science:
- Genetics
- Developmental Biology
- Medical Research
Background:
- RET tyrosine kinase receptor mutations in exon 10 are linked to MEN 2A/FMTC and Hirschsprung's disease (HSCR).
- A lack of animal models hinders understanding of the co-occurrence of MEN 2 pathology and HSCR.
- The role of RET activating mutations in developmental defects remains unclear.
Purpose of the Study:
- To investigate the RET(C620R) substitution's role in both gain- and loss-of-function RET-associated diseases.
- To generate and characterize a mouse model for the RET(C620R) mutation.
Main Methods:
- Generation of a mouse line with the C620R mutation in the Ret gene.
- Analysis of Ret(C620R) homozygotes and heterozygotes for developmental defects.
Main Results:
- Ret(C620R) homozygotes exhibit severe kidney and enteric nervous system defects, leading to perinatal lethality.
- Ret(C620R) heterozygotes display HSCR features, including gastrointestinal hypoganglionosis.
- Heterozygotes show no thyroid defects, suggesting a loss-of-function role in this context.
Conclusions:
- The Ret(C620R) allele is responsible for HSCR and impacts kidney and enteric nervous system development.
- These mice provide a valuable model for exploring therapeutic strategies for HSCR.
- The study clarifies the dual role of RET mutations in developmental disorders.
