Postnatal cerebellar defects in mice deficient in methylenetetrahydrofolate reductase.
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.
Chen
Zhoutao
Z
Departments 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.
Schwahn
Bernd C
BC
Wu
Qing
Q
He
Xinying
X
Rozen
Rima
R
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001622:Betaine / Q000008:administration & dosage / Q000494:pharmacology; D019521:Body Patterning / Q000235:genetics; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000002:abnormalities / Q000473:pathology; D002455:Cell Division; D002465:Cell Movement; D002531:Cerebellum / Q000002:abnormalities* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D000091042:Reelin Protein
D000091042:Reelin Protein; D001622:Betaine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C000717127:RELN protein, human; C000717128:Reln protein, mouse