Wnt signaling in the vertebrate central nervous system: from axon guidance to synaptic function

Abstract

Regulation of cell signaling by Wnt proteins is critical for the formation of neuronal circuits. Wnts modulate axon pathfinding, dendritic development, and synaptic assembly. Through different receptors, Wnts activate diverse signaling pathways that lead to local changes on the cytoskeleton or global cellular changes involving nuclear function. Recently, a link between neuronal activity, essential for the formation and refinement of neuronal connections, and Wnt signaling has been uncovered. Indeed, neuronal activity regulates the release of Wnt and the localization of their receptors. Wnts mediate synaptic structural changes induced by neuronal activity or experience. New emerging evidence suggests that dysfunction in Wnt signaling contributes to neurological disorders. In this article, the attention is focused on the function of Wnt signaling in the formation of neuronal circuits in the vertebrate central nervous system.

Figure 1.

Gradients of Wnts regulate axon guidance in the spinal cord. (A,B) In the cortex, a repulsive Wnt5 expressed in indusium griseum (IG) and in the glial wedge (GW) guides cortical axons through the corpus callosum (cc). Pyramidal cortical axons project to the contralateral side of the cortex by crossing the corpus callosum. After crossing to the contralateral side, these axons are repelled by Wnt5a, possibly by the expression of Ryk receptor in post-crossing axons. Wnt5a through Ryk induces the opening of IP3 and TRP channels to transiently activate CaMKII, resulting in increased axon outgrowth and repulsion. (C) A gradient of Wnt4 in the floor plate controls the direction of commissural axons. After midline crossing, commissural axons turn in an anterior direction following the attracting gradient of Wnt4. (Panels A and B are from Hutchins and Kalil 2011; reprinted, with permission, from John Wiley & Sons © 2011. Panel C is from Imondi and Thomas 2003; reprinted, with permission, from the author.)

Figure 2.

Wnt3–Ryk signaling controls the formation of topographical maps. In the retina, retinal ganglia cell axons express the Ryk receptor in a gradient from ventral high to dorsal low in the same manner as EphB. These axons project to the contralateral side and into the tectum whether they follow two opposing forces. Both Wnt3 and EphrinB1 are expressed in a gradient from medial high to lateral low. EphrinB–EphB1 forms an attractive medial-directing activity. In contrast, Wnt3–Ryk forms an opposing lateral-directing activity. (Figure is from Luo 2006; reprinted, with permission, from Nature © 2006.)

Figure 3.

Wnts promote synapse formation. On axons, binding of Wnt7a to presynaptic Fz5 leads to Dvl activation, resulting in the inhibition of GSK3β. This, in turn, promotes the recruitment of synaptic vesicles and active-zone proteins to future synaptic sites. On the postsynaptic dendrite, Wnt5a triggers the clustering of PSD-95 and promotes the formation of excitatory synapses. Wnt5a also increases the clustering of GABA_AR at inhibitory synapses.

Figure 4.

Neuronal activity regulates the membrane insertion of Fz5 receptors and their localization to synapses. In hippocampal neurons, surface Fz5 is localized to synaptic and extrasynaptic sites under basal conditions. Increased neuronal firing induced by high-frequency stimulation (HFS) increases the mobilization of Fz5 to the cell surface and in particular to the surface of synapses. Blockade of endogenous Wnt factors with the soluble extracellular domain of Fz5 (CRD-Fz5) suppresses the effect of HFS on Fz5 localization. Importantly, CRD-Fz5 completely blocks activity-induced synapse formation as indicated by the decrease in the colocalization of presynaptic vesicle markers and NMDARs.