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KIT is required for hepatic function during mouse post-natal development
Laetitia Magnol1, Marie-Clémence Chevallier, Valérie Nalesso
1Institut de Transgénose, TAAM, UPS44, IEM UMR6218, CNRS, Université Orléans, Orléans, France. magnol@cnrs-orleans.fr <magnol@cnrs-orleans.fr>
Background:
The Kit gene encodes a receptor tyrosine kinase involved in various biological processes including melanogenesis, hematopoiesis and gametogenesis in mice and human. A large number of Kit mutants has been described so far showing the pleiotropic phenotypes associated with partial loss-of-function of the gene. Hypomorphic mutations can induce a light coat color phenotype while complete lack of KIT function interferes with embryogenesis. Interestingly several intermediate hypomorphic mutations induced in addition growth retardation and post-natal mortality.
Results:
In this report we investigated the post-natal role of Kit by using a panel of chemically-induced hypomorphic mutations recently isolated in the mouse. We found that, in addition to the classical phenotypes, mutations of Kit induced juvenile steatosis, associated with the downregulation of the three genes, VldlR, Lpin1 and Lpl, controlling lipid metabolism in the post-natal liver. Hence, Kit loss-of-functions mimicked the inactivation of genes controlling the hepatic metabolism of triglycerides, the major source of energy from maternal milk, leading to growth and viability defects during neonatal development.
Conclusion:
This is a first report involving KIT in the control of lipid metabolism in neonates and opening new perspectives for understanding juvenile steatosis. Moreover, it reinforces the role of Kit during development of the liver and underscores the caution that should be exerted in using KIT inhibitors during anti-cancer treatment.
Insights
Kit mutations cause juvenile steatosis in mice by disrupting lipid metabolism genes in the liver, impacting neonatal growth and survival. This highlights Kit's role in liver development and neonatal health.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- The Kit gene encodes a receptor tyrosine kinase crucial for melanogenesis, hematopoiesis, and gametogenesis.
- Kit mutations lead to diverse phenotypes, from coat color changes to embryonic lethality.
- Intermediate hypomorphic mutations can cause growth retardation and post-natal mortality.
Purpose of the Study:
- Investigate the post-natal role of Kit using chemically-induced hypomorphic mutations in mice.
- Determine the impact of Kit loss-of-function on neonatal development and metabolism.
Main Methods:
- Utilized a panel of chemically-induced hypomorphic Kit mutations in mice.
- Analyzed post-natal phenotypes, focusing on liver and lipid metabolism.
- Examined gene expression related to triglyceride metabolism.
Main Results:
- Kit mutations induced juvenile steatosis, a condition of fat accumulation in the liver.
- Observed downregulation of VldlR, Lpin1, and Lpl genes involved in lipid metabolism.
- Kit loss-of-function mimicked inactivation of triglyceride metabolism genes, causing neonatal growth and viability defects.
Conclusions:
- This study is the first to link KIT to neonatal lipid metabolism and juvenile steatosis.
- Reinforces Kit's essential role in liver development.
- Suggests caution when using KIT inhibitors in anti-cancer treatments due to potential developmental impacts.
