Control of dendritic development by theDrosophila fragile X-relatedgene involves the small GTPase Rac1

Abstract

Fragile X syndrome is caused by loss-of-function mutations in the fragile X mental retardation 1 gene. How these mutations affect neuronal development and function remains largely elusive. We generated specific point mutations or small deletions in the Drosophila fragile X-related (Fmr1) gene and examined the roles of Fmr1 in dendritic development of dendritic arborization (DA) neurons in Drosophila larvae. We found that Fmr1 could be detected in the cell bodies and proximal dendrites of DA neurons and that Fmr1loss-of-function mutations increased the number of higher-order dendritic branches. Conversely, overexpression of Fmr1 in DA neurons dramatically decreased dendritic branching. In dissecting the mechanisms underlying Fmr1 function in dendrite development, we found that the mRNA encoding small GTPase Rac1 was present in the Fmr1-messenger ribonucleoprotein complexes in vivo. Mosaic analysis with a repressor cell marker (MARCM) and overexpression studies revealed that Rac1 has a cell-autonomous function in promoting dendritic branching of DA neurons. Furthermore, Fmr1 and Rac1 genetically interact with each other in controlling the formation of fine dendritic branches. These findings demonstrate that Fmr1 affects dendritic development and that Rac1 is partially responsible for mediating this effect.

Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

“…Dendritic arbors of mutant larval body wall sensory neurons show increased higher-order branching, but remain restricted within their usual segment boundaries. Hence, the overall footprint of the arbor is normal, but within that region there are more terminal branches [Lee et al, 2003]. For both the motor neuron axon terminals and the sensory neuron dendrites, overexpression of wild-type dFMRP induces the corresponding opposite phenotypes, consistent with the conclusion that dfmr1 wild-type function is to limit the extent and complexity of a neuron's terminal arbors, whether axonal or dendritic.…”

“…The cellular neural phenotypes of dfmr1 mutant flies are qualitatively similar to the mammalian ones, with a common-but not universal-theme of dendritic and axonal overgrowth in CNS and PNS, as well as pathfinding errors [Zhang et al, 2001;Dockendorff et al, 2002;Morales et al, 2002;Lee et al, 2003;Michel et al, 2004;Pan et al, 2004]. The only neurons for which both axonal and dendritic morphologies have been examined in dfmr1 mutants are those of the mushroom bodies, a brain region well known for its role in many forms of associative learning and memory [Zars, 2000;Roman and Davis, 2001;Heisenberg, 2003].…”

“…It is found throughout the central nervous system (CNS) and peripheral nervous system (PNS) of developing and mature animals, primarily in the cytoplasm of (probably all) neuronal somata [Zhang et al, 2001;Morales et al, 2002;Lee et al, 2003;Pan et al, 2004], but not in glia. Immunoelectron microscopy localization methods would be required to rule out small amounts of dFMRP in neuronal nuclei or near postsynaptic sites, as was found in mammals [Feng et al, 1997].…”

Rho-linked genes and neurological disorders

“…A first link between FRAXA and Rho GTPases was found in Drosophila. [53]. Lee et al demonstrated that the mRNA encoding dRac1 is present in the dFmr1-mRNP complexes in vivo [53].…”

“…[53]. Lee et al demonstrated that the mRNA encoding dRac1 is present in the dFmr1-mRNP complexes in vivo [53]. Furthermore, they provided evidence that dFmr1 exert its effect on dendritic elaboration and branching at least in part by acting on dRac1.…”