This application seeks renewed funding for a joint project between the Nelson, Oostra and Paylor groups to create and study mouse models for human Fragile X syndrome.
Prior aims of the project sought to develop and perform initial characterization of mice carrying conditional (Cre-lox) alleles at each of the 3 FMR1-like genes present in the mouse genome. Progress has been excellent; Fxr2 knockouts have been characterized, and models carrying conditional alleles have been created for Fmr1 and Fxr1. Double knockouts of Fmr1 and Fxr2 have been created; these show enhanced phenotypes beyond those found in the single mutants. Moreover, a unique circadian rhythm defect has been observed in double knockouts-these animals are hyperactive and show no rhythm in light/dark or dark/dark cycles. Fxr1 loss of function results in neonatal lethality, while animals with reduced levels of Fxr1 are affected, but viable. Mouse models for the human Fragile X premutation-associated tremor ataxia syndrome (termed FXTAS) have also been developed and are being characterized. These models recapitulate several aspects of this late onset neurodegenerative disorder. These studies offer the opportunity to create and characterize mouse models for genetic disorders (Fragile X syndrome and FXTAS) that result from a common human mutation. Such models will allow the determination of a number of the functions of the FMR1 class of proteins, and provide a resource for other groups interested in utilizing such models to test hypotheses regarding Fmr1 function and the consequences of its absence, as well as the newly described FXTAS disorder. This renewal request seeks to continue these studies through the pursuit of the following specific aims: 1) Development of models and assays for testing FMR1 and paralog functions in mice. 2) Development and use of mouse models to determine the mechanistic basis of Fragile X-premutation-associated tremor ataxia syndrome. Successful completion of these aims will allow the definition of function and dysfunction in Fragile X syndrome and FXTAS.
| Levenga, Josien; Hayashi, Shigemi; de Vrij, Femke M S et al. (2011) AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome. Neurobiol Dis 42:311-7 |
| Whitman, Samantha A; Cover, Cathleen; Yu, Lily et al. (2011) Desmoplakin and talin2 are novel mRNA targets of fragile X-related protein-1 in cardiac muscle. Circ Res 109:262-71 |
| Guo, Weixiang; Allan, Andrea M; Zong, Ruiting et al. (2011) Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning. Nat Med 17:559-65 |
| Willemsen, R; Levenga, J; Oostra, B A (2011) CGG repeat in the FMR1 gene: size matters. Clin Genet 80:214-25 |
| Levenga, Josien; de Vrij, Femke M S; Oostra, Ben A et al. (2010) Potential therapeutic interventions for fragile X syndrome. Trends Mol Med 16:516-27 |
| Brouwer, J R; Willemsen, R; Oostra, B A (2009) The FMR1 gene and fragile X-associated tremor/ataxia syndrome. Am J Med Genet B Neuropsychiatr Genet 150B:782-98 |
| Oostra, Ben A; Willemsen, Rob (2009) FMR1: a gene with three faces. Biochim Biophys Acta 1790:467-77 |
| Brouwer, Judith R; Willemsen, Rob; Oostra, Ben A (2009) Microsatellite repeat instability and neurological disease. Bioessays 31:71-83 |
| Zhang, Jing; Hou, Lingfei; Klann, Eric et al. (2009) Altered hippocampal synaptic plasticity in the FMR1 gene family knockout mouse models. J Neurophysiol 101:2572-80 |
| Hashem, Vera; Galloway, Jocelyn N; Mori, Mayra et al. (2009) Ectopic expression of CGG containing mRNA is neurotoxic in mammals. Hum Mol Genet 18:2443-51 |
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