Wnt5a modulates dendritic spine dynamics through the regulation of Cofilin via small Rho GTPase activity in hippocampal neurons

Abstract

Dendritic spines are small, actin‐rich protrusions that act as the receiving sites of most excitatory inputs in the central nervous system. The remodeling of the synapse architecture is mediated by actin cytoskeleton dynamics, a process precisely regulated by the small Rho GTPase family. Wnt ligands exert their presynaptic and postsynaptic effects during formation and consolidation of the synaptic structure. Specifically, Wnt5a has been identified as an indispensable synaptogenic factor for the regulation and organization of the postsynaptic side; however, the molecular mechanisms through which Wnt5a induces morphological changes resulting from actin cytoskeleton dynamics within dendritic spines remain unclear. In this work, we employ primary rat hippocampal cultures and HT22 murine hippocampal neuronal cell models, molecular and pharmacological tools, and fluorescence microscopy (laser confocal and epifluorescence) to define the Wnt5a‐induced molecular signaling involved in postsynaptic remodeling mediated via the regulation of the small Rho GTPase family. We report that Wnt5a differentially regulates the phosphorylation of Cofilin in neurons through both Ras‐related C3 botulinum toxin substrate 1 and cell division cycle 42 depending on the subcellular compartment and the extracellular calcium levels. Additionally, we demonstrate that Wnt5a increases the density of dendritic spines and promotes their maturation via Ras‐related C3 botulinum toxin substrate 1. Accordingly, we find that Wnt5a requires the combined activation of small Rho GTPases to increase the levels of filamentous actin, thus promoting the stability of actin filaments. Altogether, these results provide evidence for a new mechanism by which Wnt5a may target actin dynamics, thereby regulating the subsequent morphological changes in dendritic spine architecture.

ERVWE1 Reduces Hippocampal Neuron Density and Impairs Dendritic Spine Morphology through Inhibiting Wnt/JNK Non-Canonical Pathway via miR-141-3p in Schizophrenia

“…Wnt5a activates Arp2 through RAC1 and WAVE1 [ 23 , 25 , 43 , 52 , 53 ]. Our clinical data implied that Wnt5a was positively correlated with Arp2.…”

“…Our experiments also confirmed that wnt5a was a target gene of miR-141-3p. In vitro and vivo models indicate that Wnt5a modulates dendritic spine dynamics [ 25 ] and promotes postsynaptic development [ 81 ] in hippocampal neurons.…”

“…Wnt5a, RAC1, WAVE1 and Arp2 are critical regulators in the development of dendritic spines [ 20 , 25 , 87 , 96 ]. Wnt5a, expressed early in neuronal development, increases dendritic spine density, regulates dendritic spine formation, and stimulates dendritic spine morphogenesis [ 25 ]. RAC1 influence the morphological maturation of dendritic spines [ 87 ].…”

“…The Rho GTPase Rac family small GTPase 1 (RAC1) activates Arp2/3 complex-mediated actin polymerization through constitutive phosphorylation of Wiskott-Aldrich syndrome protein (WASP) at serine 483 and 484 [ 22 , 23 ]. Recent evidence reveals that Wingless-type family member 5A (Wnt5a) promotes Arp2/3 association at adherens junctions [ 24 ] and increases the density and maturity of dendritic spines [ 25 ]. A gene expression study suggests Wnt5a signaling is implicated in the etiology of schizophrenia [ 26 ].…”

Genetic disorders of cellular trafficking

“…For this function, the participation of adaptor proteins such as the TRACK proteins is important. Additionally, the participation of small GTPases such as Rab and Rho proteins in the cytoskeleton dynamics and the dynamin superfamily is gaining importance as determinants of both pathological and physiological conditions [57].…”