title: Delayed myelination in a mouse model of fragile X syndrome.
abstract: Fragile X Syndrome is the most common inherited cause of autism. Fragile X mental retardation protein (FMRP), which is absent in fragile X, is an mRNA binding protein that regulates the translation of hundreds of different mRNA transcripts. In the adult brain, FMRP is expressed primarily in the neurons; however, it is also expressed in developing glial cells, where its function is not well understood. Here, we show that fragile X (Fmr1) knockout mice display abnormalities in the myelination of cerebellar axons as early as the first postnatal week, corresponding roughly to the equivalent time in human brain development when symptoms of the syndrome first become apparent (1-3 years of age). At postnatal day (PND) 7, diffusion tensor magnetic resonance imaging showed reduced volume of the Fmr1 cerebellum compared with wild-type mice, concomitant with an 80-85% reduction in the expression of myelin basic protein, fewer myelinated axons and reduced thickness of myelin sheaths, as measured by electron microscopy. Both the expression of the proteoglycan NG2 and the number of PDGFRα+/NG2+ oligodendrocyte precursor cells were reduced in the Fmr1 cerebellum at PND 7. Although myelin proteins were still depressed at PND 15, they regained wild-type levels by PND 30. These findings suggest that impaired maturation or function of oligodendrocyte precursor cells induces delayed myelination in the Fmr1 mouse brain. Our results bolster an emerging recognition that white matter abnormalities in early postnatal brain development represent an underlying neurological deficit in Fragile X syndrome.
authors.forename: Laura K K
authors.initials: LK
authors.lastname: Pacey
authors.forename: Ingrid C Y
authors.initials: IC
authors.lastname: Xuan
authors.forename: Sihui
authors.initials: S
authors.lastname: Guan
authors.forename: Dafna
authors.initials: D
authors.lastname: Sussman
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Christian
authors.initials: C
authors.lastname: Thomsen
authors.forename: David R
authors.initials: DR
authors.lastname: Hampson
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D009836:Oligodendroglia / Q000166:cytology
chemical_list: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse