Wnt signaling regulates neuronal development

ROSSO, SB

Carlos Paz, Cordoba, Argentina

Conferencia; XLIV Reunión Annual de la Sociedad Argentina de Investigaciones Bioquímicas (SAIB); 2008

Sociedad Argentina de Investigaciones Bioquímicas

The development and functions of the nervous system depend on the establishment of specific neuronal connections. Both intrinsic programs and extrinsic factors modulate neuronal development. Neuroblasts perceive the presence of neurotrophic factors present in the extracellular media (such as IGF-1, BDNF, NGF and Wnts), which regulate neuronal differentiation, polarization and migration. Wnt factors are secreted glycoproteins that play a crucial role on neuronal maturation as they have been implicated in axon guidance and behaviour, dendritogenesis and synapses formation. Wnts signalling through Frizzled (Fz) receptor activates Dishevelled (DVL), a first intracellular effector. Wnt-DVL signalling can activate three different pathways: the canonical or b-catenin pathway, the planar cell polarity pathway and the calcium pathway. In this work, we show the roles of Wnt-DVL on neuronal differentiation and maturation. Wnt7b regulates dendrite development and complexity in hippocampal neurons. Particularly, Wnt and DVL increase dendrite arborisation through the activation of Rac and JNK. Consistent with these findings, hippocampal neurons from Dvl1 mutant mice exhibit reduced dendritic arborisation and dominant-negative forms of Rac or JNK block Dvl-mediated dendritic growth. These findings suggest that Wnt pathway regulates dendritic maturation. However, little is known about the role of WNT signalling earlier, particularly on the initial axonal outgrowth and the establishment of neuronal polarity. Currently, we are investigating the role of Wnt factors, their Frizzled receptors and DVL on these phenomena. We found that undifferentiated neurons challenged with Wnt3a or overexpressing DVL develope multiple and more complex axons. Wnt3a seems to regulate axon formation through a non-canonical pathway. Importantly, Wnt3a activates PI3K in cultured neurons and in purified growth cones particles suggesting that Wnt3a may act through the same pathway as IGF-1 (previously defined as an essential factor for the establishment of neuronal polarity). In addition, Wnt3a cross-activates IGF-1 receptors in neurons and the Wnt effects on axons are blocked by an IGF-1 receptor blocking antibody. These findings suggest a possible parallelism between the two signalling systems: Wnt-Fz-DVL and IGF-1- IGF receptor- PI3K on axon formation. We conclude that the Wnt-DVL pathway is essential for neuronal development from axon formation to dendrite maturation by activating different secondary signalling cascades.