Wnt signaling in vertebrate neural development and function

Abstract

Members of the Wnt family of secreted signaling proteins influence many aspects of neural development and function. Wnts are required from neural induction and axis formation to axon guidance and synapse development, and even help modulate synapse activity. Wnt proteins activate a variety of downstream signaling pathways and can induce a similar variety of cellular responses, including gene transcription changes and cytoskeletal rearrangements. This review provides an introduction to Wnt signaling pathways and discusses current research on their roles in vertebrate neural development and function.

Fig. 1

The Wnt Signal Transduction Pathways. a A brief summary of the canonical Wnt/β-catenin signaling pathway. When Wnt binds to a complex of the Fz and LRP co-receptors, that causes translocation of Axin and Dvl to the membrane to form a signalosome, along with concomitant dissociation of the β-catenin destruction complex that includes Axin, APC, GSK3β and other proteins not included in this diagram. The outcome is to decrease GSK3β-mediated phosphorylation of β-catenin, which otherwise targets β-catenin for proteasome-mediated degradation. In the absence of this degradation, β-catenin accumulates in the cytoplasm and translocates to the nucleus where it interacts with Lef/Tcf transcription factors to regulate target gene transcription. b The divergent canonical Wnt pathway. The same upstream events as the canonical Wnt/β-catenin signaling pathway that inhibit GSK3β-mediated phosphorylation of β-catenin also inhibit GSK3β-mediated phosphorylation of microtubule associated proteins such as MAP1B, allowing for their regulation of cytoskeletal rearrangements and stability. c The Wnt/PCP pathway. Wnt-Fz binding leads to changes in the interaction and subcellular localization of several transmembrane and cytoplasmic proteins. Through cellular and biochemical mechanisms that remain to be elucidated, this leads to activation of downstream mediators including JNK, RhoA, and Rac1, leading to dynamic alterations in actin and microtubule cytoskeletal components. This pathway is subject to down-regulation through Vangl-mediated recruitment of Prickle, a Dvl-binding protein that inhibits Fz-recruitment of Dvl. d The Wnt/Ca²⁺ pathway. Wnt-Fz binding activates PLC in a Dvl-dependent manner leading to a transient increase in cytoplasmic calcium levels and activation of PKC and CaM-KII. PKC has multiple downstream intracellular effectors including transcriptional activators; CaMKII promotes nuclear import and activity of NFAT. e The FNI pathway. Wnt-Fz binding causes internalization, cleavage, and subsequent GRIP-dependent nuclear trafficking of Fz

Fig. 2

Wnt signaling in the developing mammalian brain. a Anterior-posterior specification of the neural plate and neural tube is dependent on graded Wnt signaling. A posterior-high to anterior-low extracellular gradient of Wnt, along with anterior expression of the secreted Wnt antagonist, Sfrp1, maintains a posterior-high to anterior-low gradient of Wnt signaling activity critical for anterior-posterior axis specification of the developing neural tube. b Expression profile of Wnts in the developing mammalian brain. A diagram of the prosencephalon/forebrain (green), mesencephalon/midbrain (blue), rhombencephalon/hindbrain (orange), and spinal cord (purple), and the Wnt genes known to be expressed in each of these tissues during early embryonic development. c Wnt4 and Wnt7b act as chemoattractants for postcrossing commissural axons. Dorsal spinal commissural neurons project axons ventrally toward the floor plate, where they respond to anterior-high to posterior-low gradients of both Wnt4 and Wnt7b that serve as attractive cues to guide postcrossing commissural axons anteriorly

Fig. 3

Wnt7a signals bidirectionally through divergent pathways to influence both presynaptic and postsynaptic assembly and to promote excitatory synapse formation and function. Wnt7a is secreted by postsynaptic dendrites of cerebellar granule cells and hippocampal neurons. Wnt7a is sufficient to induce presynaptic axon remodeling and Synapsin-1 clustering in a GSK3β-dependent manner, potentially through MAP1B-mediated cytoskeletal changes. In addition, Wnt7a signals through the Wnt/Ca²⁺ pathway at the presynapse to increase frequency of mEPSCs. Wnt7a secreted by dendrites also initiates postsynaptic Wnt signaling activity, regulating dendrite growth in a CaMKII dependent manner and increasing postsynaptic PSD95 clustering. Other Wnt ligands, such as Wnt5a, exert similarly complex activities on both sides of the synapse (see text)