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Postnatal cerebellar defects in mice deficient in methylenetetrahydrofolate reductase
Author(s) -
Chen Zhoutao,
Schwahn Bernd C.,
Wu Qing,
He Xinying,
Rozen Rima
Publication year - 2005
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2005.05.007
Subject(s) - methylenetetrahydrofolate reductase , cerebellum , endocrinology , purkinje cell , medicine , biology , neurogenesis , granule cell , cerebellar cortex , central nervous system , microbiology and biotechnology , dentate gyrus , biochemistry , gene , genotype
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.