Wnt signalling through Dishevelled regulates dendritic development

SILVANA B. ROSSO

Los Cocos, Cordoba, Argentina

Conferencia; XXI Reunion Anual de la Sociedad Argentina de Investigacion en Neurociencias; 2006

Sociedad Argentina de Investigacion en Neurociencias (SAN)

Wnt proteins can function as axon guidance molecules and as target-derived signals that regulate axonal behavior and synapses formation. Wnts signalling is transduced by the Frizzled (Fz) family of serpentine transmembrane receptors in conjunction with LRP family of co-receptors (canonical pathway). However, Wnt proteins can signal through different pathways. In neurons, WNTs induce axonal remodelling through the activation of DVL and the subsequent inhibition of GSK-3b and this effect is associated with an increase in microtubule stability. Given the effects on axonal behavior, we examined whether WNT signalling also regulates dendritic development. Dendritic arborization is required for proper neuronal connectivity. Rho GTPases have been implicated in the regulation of dendrite initiation, growth, branching and maintenance. However, the signalling pathways that impinge on these molecular switches remain poorly understood. Here we show that Wnt7b, which is expressed in the mouse hippocampus, increases dendritic branching in cultured hippocampal neurons.  This effect is mimicked by expression of Dishevelled (Dvl) and is blocked by Sfrp1, a secreted Wnt antagonist. Consistent with these findings, hippocampal neurons from Dvl1 mutant mice exhibit reduced dendritic arborization. Activation of the canonical Wnt-Gsk3ß pathway does not affect dendritic development. In contrast, Wnt7b and Dvl activate Rac and JNK in hippocampal neurons.  Importantly, dominant-negative Rac, dominant negative JNK or inhibition of JNK blocks Dvl-mediated dendritic growth. These findings demonstrate a novel function for the non-canonical Wnt pathway in dendrite development and identify Dvl as a key regulator of dendritogenesis. Dvl functions as a molecular link in the signal transduction between extracellular factors and Rho GTPases during dendritic morphogenesis. Currently, we are trying to identify the specific receptor for Wnt7b mediating the dendritogenic effect by binding and functional assays. Our findings suggest that Fz7 can function as a receptor for Wnt7b to regulate dendritic morphogenesis.