Rac1 and Fragile X Syndrome

Abstract

The most common form of inherited mental retardation is associated with loss-of-function (LOF) mutations in the fragile X mental retardation 1 ( FMR1 ) gene. Although FMR1 encodes an RNA-binding protein that associates with mRNAs and ribosomes, its molecular function and role in nervous system development have not been clear. The homologous protein in Drosophila , Fmr1, is highly expressed in dendritic arborization (DA) neurons of the peripheral nervous system. Lee et al. studied DA neurons from Fmr1-deficient flies and determined that the protein regulates dendritic branching during development. Fmr1 localized to the cytoplasm and dendrites of DA neurons. Fmr1 LOF mutant embryos exhibited increased dendritic processes, whereas embryos overexpressing Fmr1 had reduced dendritic branch formation. mRNA encoding the small guanosine triphosphatase Rac1 immunoprecipitated with Fmr1 from larval lysates. DA neurons in larva expressing a null allele of Rac1 developed fewer dendritic branches than wild-type neurons, similar to the phenotype observed when Fmr1 was overexpressed. Rac1 overexpression promoted dendritic branching and partially rescued the effects of Fmr1 overexpression, indicating that Rac1 is a downstream component of Fmr1 function. Because Rac1 has been implicated in controlling cell morphology, the authors propose that local regulation of Rac1 expression by Fmr1 in neurons may control dendritic branching during development. A. Lee, W. Li, K. Xu, B. A. Bogert, K. Su, F.-B. Gao, Control of dendritic development by the Drosophila fragile X-related gene involves the small GTPase Rac1. Development 130 , 5543-5552 (2003). [Abstract] [Full Text]