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RET-deficient mice: an animal model for Hirschsprung's disease and renal agenesis
A Schuchardt1, V D'Agati, L Larsson-Blomberg
1Department of Genetics and Development, Columbia University, New York, NY, USA.
Abstract:
Receptor tyrosine kinases play a critical role in transducing signals involved in cell growth and differentiation. The c-ret proto-oncogene is a member of the receptor tyrosine kinase gene superfamily originally identified by its transforming ability. Somatic mutations of c-ret are responsible for a large proportion of thyroid papillary carcinomas, while germ-line mutations are responsible for multiple endocrine neoplasia types 2A and 2B, dominantly inherited cancer syndromes characterized by multiple tumours of neuroectodermal origin. In addition to its role in tumour formation. c-ret is thought to have a developmental role since mutations of the gene have been implicated in the aetiology of Hirschsprung's syndrome (congenital megacolon). A targeted mutation in the murine c-ret locus shows that the ret receptor is required for normal development of two lineally unrelated systems, the excretory system and the enteric nervous system.
Insights
The c-ret proto-oncogene is crucial for cell growth and development. Mutations in this gene are linked to thyroid cancer and Hirschsprung
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- Receptor tyrosine kinases (RTKs) regulate cell growth and differentiation.
- The c-ret proto-oncogene, an RTK, is implicated in various cancers and developmental disorders.
- Germline and somatic mutations in c-ret are associated with thyroid cancer and Hirschsprung's syndrome.
Purpose of the Study:
- To investigate the role of the c-ret proto-oncogene in cellular signaling and development.
- To understand the implications of c-ret mutations in human diseases.
Main Methods:
- Analysis of the c-ret proto-oncogene's function within the receptor tyrosine kinase superfamily.
- Examination of mutation data from thyroid papillary carcinomas and multiple endocrine neoplasia syndromes.
- Investigation of a targeted mutation in the murine c-ret locus.
Main Results:
- Somatic c-ret mutations drive a significant portion of thyroid papillary carcinomas.
- Germline c-ret mutations cause inherited cancer syndromes (MEN2A/2B) and Hirschsprung's syndrome.
- Murine c-ret mutations reveal its essential role in the development of the excretory and enteric nervous systems.
Conclusions:
- The c-ret proto-oncogene is vital for both oncogenesis and normal embryonic development.
- Dysregulation of c-ret signaling contributes to diverse pathologies, including cancer and congenital abnormalities.
- Targeted studies in model organisms confirm the broad developmental significance of the ret receptor.