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Published on: July 14, 2016
Mice defective in Trpm6 show embryonic mortality and neural tube defects
Roxanne Y Walder1, Baoli Yang, John B Stokes
1Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
Insights
Mice lacking the TRPM6 ion channel gene (Trpm6) exhibited severe developmental issues, including neural tube defects like spina bifida occulta. This highlights TRPM6's crucial role in embryonic development.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Defective TRPM6 causes hypomagnesemia with secondary hypocalcemia, leading to severe developmental issues in children.
- TRPM6 is an ion channel with a kinase domain crucial for cellular function.
Purpose of the Study:
- To investigate the function of TRPM6 by creating and analyzing a mouse model lacking the Trpm6 gene.
- To understand the in vivo role of TRPM6 in mammalian development.
Main Methods:
- Generation of Trpm6 knockout (Trpm6(-/-)) mice.
- Phenotypic analysis of Trpm6(-/-) mice, including survival rates, developmental abnormalities, and electrolyte levels.
- Analysis of Trpm6(+/-) mice to assess heterozygous effects.
Main Results:
- Trpm6(-/-) mice showed extremely low survival rates, with many dying during embryonic development.
- Surviving Trpm6(-/-) mice exhibited neural tube defects, including exencephaly and spina bifida occulta.
- Trpm6(+/-) mice had slightly reduced plasma magnesium and some premature deaths, indicating haploinsufficiency.
Conclusions:
- Absence of TRPM6 leads to severe developmental defects in mice, distinct from the human phenotype.
- TRPM6 plays a critical, previously unrecognized role in neural tube closure during embryonic development.
- Trpm6(-/-) mice represent a valuable model for studying spina bifida occulta and TRPM6 function.
Abstract:
The syndrome of hypomagnesemia with secondary hypocalcemia is caused by defective TRPM6. This protein is an ion channel that also contains a kinase in its C-terminus. It is usually diagnosed in childhood and, without treatment with supplemental Mg, affected children suffer from mental retardation, seizures and retarded development. We developed a mouse lacking Trpm6 in order to understand in greater detail the function of this protein. In contrast to our expectations, Trpm6(-/-) mice almost never survived to weaning. Many mice died by embryonic day 12.5. Most that survived to term had neural tube defects consisting of both exencephaly and spina bifida occulta, an unusual combination. Feeding dams a high Mg diet marginally improved offspring survival to weaning. The few Trpm6(-/-) mice that survived were fertile but matings between Trpm6(-/-) mice produced no viable pregnancies. Trpm6(+/-) mice had normal electrolytes except for modestly low plasma [Mg]. In addition, some Trpm6(+/-) mice died prematurely. Absence of Trpm6 produces an apparently different phenotype in mice than in humans. The presence of neural tube defects identifies a previously unsuspected role of Trpm6 in effecting neural tube closure. This genetic defect produces one of very few mouse models of spina bifida occulta. These results point to a critical role of Trpm6 in development and suggest an important role in neural tube closure.
