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Postnatal cerebellar defects in mice deficient in methylenetetrahydrofolate reductase
Zhoutao Chen1, Bernd C Schwahn, Qing Wu
1Departments of Human Genetics, Pediatrics and Biology, McGill University and Montreal Children's Hospital Research Institute, 4060 Ste. Catherine West, Room 200, Montreal, Que., Canada H3Z 2Z3.
Abstract:
Patients with severe deficiency of methylenetetrahydrofolate reductase (MTHFR) suffer from a wide variety of neurological problems, which can begin in the neonatal period. MTHFR is a critical enzyme in folate metabolism; the product of the MTHFR reaction, 5-methyltetrahydrofolate, is required for homocysteine remethylation to methionine and synthesis of S-adenosylmethionine (SAM). To understand the mechanisms by which MTHFR deficiency leads to significant neuropathology, we examined early postnatal brain development in mice with a homozygous knockout of the Mthfr gene. These mice displayed a dramatically reduced size of the cerebellum and cerebral cortex, with enlarged lateral ventricles. Mthfr deficiency affected granule cell maturation, but not neurogenesis. Depletion of external granule cells and disorganization of Purkinje cells were mainly confined to the anterior lobules of mutant cerebella. Decreased cellular proliferation and increased cell death contributed to the granule cell loss. Reduced expression of Engrailed-2 (En2), Reelin (Reln) and inositol 1,4,5-triphosphate receptor type 1 (Itpr1) genes was observed in the cerebellum. Supplementation of Mthfr(+/-) dams with an alternate methyl donor, betaine, reduced cerebellar abnormalities in the Mthfr(-/-) pups. Our findings suggest that MTHFR plays a role in cerebellar patterning, possibly through effects on proliferation or apoptosis.
Insights
Methylenetetrahydrofolate reductase (MTHFR) deficiency causes severe neurological issues. In mice, MTHFR deficiency impairs cerebellar development by affecting cell maturation and survival, highlighting MTHFR
Area of Science:
- Biochemistry
- Neuroscience
- Developmental Biology
Background:
- Severe methylenetetrahydrofolate reductase (MTHFR) deficiency leads to significant neurological problems from infancy.
- MTHFR is crucial for folate metabolism, producing 5-methyltetrahydrofolate for homocysteine remethylation and S-adenosylmethionine (SAM) synthesis.
Purpose of the Study:
- To investigate the mechanisms by which MTHFR deficiency causes neuropathology.
- To examine the effects of MTHFR deficiency on early postnatal brain development in a mouse model.
Main Methods:
- Generated Mthfr gene knockout mice (Mthfr-/-) to study homozygous deficiency.
- Analyzed cerebellar and cerebral cortex development, including cell maturation, proliferation, and apoptosis.
- Assessed gene expression of key developmental markers (Engrailed-2, Reelin, Itpr1).
- Investigated the therapeutic potential of betaine supplementation in Mthfr(+/-) dams.
Main Results:
- Mthfr-/- mice exhibited significantly smaller cerebella and cerebral cortices, with enlarged lateral ventricles.
- Granule cell maturation was impaired, characterized by depletion of external granule cells and Purkinje cell disorganization, primarily in anterior lobules.
- Reduced cellular proliferation and increased cell death contributed to granule cell loss.
- Expression of Engrailed-2, Reelin, and Itpr1 genes was decreased in the cerebellum.
- Betaine supplementation in Mthfr(+/-) dams ameliorated cerebellar abnormalities in Mthfr(-/-) pups.
Conclusions:
- MTHFR plays a critical role in cerebellar patterning and development.
- MTHFR deficiency impacts neuronal proliferation and apoptosis, leading to neuropathology.
- Betaine may offer a potential therapeutic strategy for MTHFR-related neurological disorders.
