Project Details
Projekt
Regulation of the WAVE-complex actin nucleation and physiology
Applicant
Professor Dr. Walter Witke
Subject Area
Cell Biology
Term
from 2010 to 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 170444030
The WAVE-complex is a pentamer with Sra1/Cyfip (Cytoplasmic Fragile-X interacting Protein) as an indispensable subunit. Activation of the WAVE-complex is thought to trigger Arp2/3 and to nucleate actin polymerization. However, in human the relevance and mechanisms of WAVE-complex mediated actin nucleation and the link to physiology is unclear. Genetic studies in autism spectrum disorder (ASD) patients revealed that Cyfip1 is a prime susceptibility gene for autism in syndromes such as Prader-Willi and Angelman syndrome. The mechanisms leading to autism have not been defined yet and the involvement of the WAVE-complex and the actin cytoskeleton remains to be shown. We therefore propose to capitalize on conditional mouse models for Cyfip to test the hypothesis, that the WAVE-complex is linked to ASD. In human and mouse two genes, Cyfip1 and Cyfip2, have been described, and we have shown that both are found in the WAVE-complex. We have also shown that in neurons the WAVE-complex localizes to synaptic boutons and there associates tightly with the pre- and postsynaptic matrix. As part of this proposal we will characterize the function and mechanism of Cyfip, and the WAVE-complex, in synaptic actin nucleation and elucidate the physiological role in synaptic transmission. We will employ a biochemical approach to characterize the composition of the WAVE-complex in the synapse and we will define the relation to other complexes of Cyfip implicated in translational control. With the mouse model in hand we can then relate the obtained data to alterations in behaviour. The focus of these experiments will be to test paradigms of mental retardation and autism-like behaviour in copy number mutants for Cyfip1 and Cyfip2, ranging from complete deletion of both proteins in neurons, to copy number variations in heterozygous compound mutant mice. We anticipate that this project will provide insights in the nature of the WAVE-complex in a tissue context and the role in synaptic actin nucleation. Our studies also aim to resolve the question of Cyfip being a part of the WAVE-complex as well as part of the FMRP-complex and the translation machinery. These studies will shed light on the etiology of ASD and the underlying mechanisms.
DFG Programme
Priority Programmes
