WNT factors and Neuronal Polarity: Involvement of PI3K Pathway

BERNIS, ME; QUIROGA, S; ROSSO, SB

Rosario, Santa Fe, Argentina

Congreso; XLI Reunión Annual de la Sociedad Argentina de Farmacología Experimental (SAFE); 2009

Sociedad Argentina de Farmacología Experimental

Neuronal development, from the establishment of neuronal polarity to axon guidance and maturation are controlled by a combination of an intrinsic program of gene expression and by extrinsic factors (such as Wnts, BMPs, IGF-1, BDNF, and NGF). Wnt factors are secreted signalling molecules implicated in important developmental processes, as embryonic patterning, tissue polarity and cell movement. Recent works have shown that Wnts also regulate neuronal maturation as they have been implicated in axon guidance, dendritogenesis and synapses formation. Wnts through Frizzled (Fz) receptor activate Dishevelled (DVL), a first effector. Wnt-DVL signalling can signal through three different pathways: the canonical or b-catenin pathway, the planar cell polarity pathway and the calcium pathway. In this work, we study the role of WNT-DVL signalling during neuronal differentiation, particularly during axon outgrowth and the establishment of neuronal polarity. Neurons cultured in the presence of Wnt3a or expressing DVL show multiple and more complex axons. Wnt3a seems to regulate axon formation through a non-canonical pathway and this effect is blocked by sFRP (a Wnt antagonist). Importantly, Wnt3a activates PI3K in neurons and in purified growth cones particles suggesting that Wnt3a may act through the same pathway as IGF-1 (previously defined as an essential for neuronal polarity). In addition, we found that Wnt3a cross-activates the receptor of IGF-1 in neurons and in growth cones and this effect is blocked by an IGF-1R blocking antibody. These findings suggest that Wnt proteins are essential for neuronal polarity and suggest a possible parallelism between the two signalling systems: Wnt-Fz-DVL and IGF-1-IGFR-PI3K on axon formation.