A Molecular Bridge to Neuronal Morphogenesis

Science's STKE  01 Jul 2003:
Vol. 2003, Issue 189, pp. tw248-TW248
DOI: 10.1126/stke.2003.189.tw248

Fragile X syndrome, a form of hereditary mental retardation, is associated with disruption of the fragile X mental retardation gene (FMR1) and the loss of its protein product FMRP, which binds to RNA and regulates the translation of specific mRNAs. Mutations in signaling pathways involving Rho guanosine triphosphatases (Rho GTPases), which control remodeling of the actin cytoskeleton, are also associated with mental retardation and cause synaptic abnormalities similar to those observed with the loss of FMRP (see Billuart and Chelly). Two human cytoplasmic FMRP-interacting proteins (CYFIPs) had been previously identified, one of which also interacted with Rac, a member of the Rho GTPases. Schenk et al. determined that Drosophila CYFIP links Rac and FMRP pathways, thus playing a key role in the regulation of neuronal connectivity and morphogenesis. Northern and Western analyses indicated that CYFIP was expressed in the Drosophila nervous system. CYFIP mutations disrupted axonal pathfinding, growth, and branching and affected synaptic morphology (as do mutations in dFMR1 and dRac1). The authors used a glutathione-S-transferase assay in combination with coimmunoprecipitation experiments to demonstrate that dFMR1 and dRac1 both interacted with CYFIP (but not with each other). In vivo gene-dosage experiments indicated that CYFIP antagonized dRac1 and dFMR. The authors proposed a model in which dRac1-mediated inhibition of CYFIP, in combination with CYFIP-mediated inhibition of dFMR1, led to dRac1 activation of dFMR1. In this model, CYFIP provides the molecular bridge between cytoskeletal remodeling and localized translation in the regulation of neuronal connectivity and morphogenesis.

A. Schenck, B. Bardoni, C. Langmann, N. Harden, J.-L. Mandel, A. Giangrande, CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein. Neuron 38, 887-898 (2003). [Online Journal]

P. Billuart, J. Chelly, From fragile X mental retardation protein to Rac1 GTPase: New insights from fly CYFIP. Neuron 38, 843-845 (2003). [Online Journal]