IDENTIFICATION OF CRMP4 AS A CONVERGENT REGULATOR OF AXON OUTGROWTH INHIBITION
摘要
<p>The present invention relates to the identification of the cytosolic phosphoprotein CRMP4b as a protein that physically and functionally interacts with RhoA to mediate neurite outgrowth inhibition. siRNA-mediated knockdown of CRMP4 promotes neurite outgrowth on myelin substrates indicating a critical role for CRMP4 in neurite outgrowth inhibition. Disruption of CRMP4b-RhoA binding with a competitive inhibitor attenuates neurite outgrowth inhibition on myelin and aggrecan substrates. Stimulation of neuronal growth cones with Nogo leads to co-localization of CRMP4b and RhoA at discrete regions within the actin-rich central and peripheral domains of the growth cone indicative of a potential function in cytoskeletal rearrangements during neurite outgrowth inhibition. Together these data indicate that a RhoA-CRMP4b complex forms in response to inhibitory challenges in the growth cone environment and regulate cytoskeletal dynamics at distinct sites necessary for axon outgrowth inhibition. Competitive inhibition of CRMP4b-RhoA binding suggests a novel, highly specific therapeutic avenue for promoting regeneration following CNS injury.</p>
申请公布号
WO2007106991(A1)
申请公布日期
2007.09.27
申请号
WO2007CA00440
申请日期
2007.03.19
申请人
MCGILL UNIVERSITY;FOURNIER, ALYSON, E.;ALABED, YAZAN, Z.