Human Molecular Genetics Advance Access [Accepted Manuscript] published online on October 21, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp479
Murine Hippocampal Neurons Expressing Fmr1 gene Premutations Show Early Developmental Deficits and Late Degeneration
1 Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616 2 Medical Investigations of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California, Davis, CA 95616 3 Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95616 4 Department of Neurological Surgery, School of Medicine, University of California, Davis, CA 95616 5 Department of Pediatrics, UC Davis Medical center, University of California, Davis, CA 95616 6 Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands
* Correspondence to: Yucui Chen, Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, One Shields Ave, Davis, CA 95616 USA, Phone: (530) 752-2174, FAX: (530) 752-4698, E-mail: ycachen{at}ucdavis.edu
Received August 14, 2009; Revised October 9, 2009; Accepted October 15, 2009
Premutation CGG repeat expansions (155-200 CGG repeats; preCGG) within the fragile X mental retardation 1 (FMR1) gene give rise to the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), primary ovarian insufficiency (POI) and neurodevelopmental problems. Morphometric analysis of Map2B immunofluorescence reveals that neurons cultured from heterozygous female mice with preCGG repeats in defined medium display shorter dendritic lengths and fewer branches between 7 and 21 days in vitro (DIV) compared to wild type (WT) littermates. Although the numbers of synapsin and phalloidin puncta do not differ from WT, preCGG neurons possess larger puncta. PreCGG neurons display lower viability, and express elevated stress protein as they mature. PreCGG neurons have inherently different patterns of growth, dendritic complexity, and synaptic architecture discernable early in the neuronal trajectory to maturation, and may reflect a cellular basis for the developmental component of the spectrum of clinical involvement in carriers of premutation alleles. The reduced viability of preCGG neurons is consistent with the mRNA toxicity and neurodegeneration associated with FXTAS.