Semaphorin3F Drives Dendritic Spine Pruning through Rho-GTPase Signaling

Abstract

Dendritic spines of cortical pyramidal neurons are initially overproduced then remodeled substantially in the adolescent brain to achieve appropriate excitatory balance in mature circuits. Here we investigated the molecular mechanism of developmental spine pruning by Semaphorin 3F (Sema3F) and its holoreceptor complex, which consists of immunoglobulin-class adhesion molecule NrCAM, Neuropilin-2 (Npn2), and PlexinA3 (PlexA3) signaling subunits. Structure-function studies of the NrCAM-Npn2 interface showed that NrCAM stabilizes binding between Npn2 and PlexA3 necessary for Sema3F-induced spine pruning. Using a mouse neuronal culture system, we identified a dual signaling pathway for Sema3F-induced pruning, which involves activation of Tiam1-Rac1-PAK1-3 -LIMK1/2-Cofilin1 and RhoA-ROCK1/2-Myosin II in dendritic spines. Inhibitors of actin remodeling impaired spine collapse in the cortical neurons. Elucidation of these pathways expands our understanding of critical events that sculpt neuronal networks and may provide insight into how interruptions to these pathways could lead to spine dysgenesis in diseases such as autism, bipolar disorder, and schizophrenia.

Modelling and Refining Neuronal Circuits with Guidance Cues: Involvement of Semaphorins

“…By contrast, those spines in which NRP2 clusters with NrCAM are pruned by binding with SEMA3F [ 67 , 68 ]. As shown with structural and functional experiments, SEMA3F induces surface clustering of NrCAM/NRP2/PLXNA3, activating Rac1 and RhoA pathways [ 70 ]. Specifically, upon binding, PLXNA3 intracellular domain inactivates Rap1, allowing activation of the RhoA-ROCK1/2-Myosin II pathway for actin remodeling.…”

“…Specifically, upon binding, PLXNA3 intracellular domain inactivates Rap1, allowing activation of the RhoA-ROCK1/2-Myosin II pathway for actin remodeling. Concomitantly, Tiam1 is recruited, activating the Rac1-PAK-LIMK-Cofilin pathway to provide for spine destabilization and finally cytoskeletal disassembly [ 70 ]. Although the regulatory mechanism remains to be fully explained, it is interesting to notice that both SEMA3B and SEMA3F release is activity-dependent [ 69 , 70 ].…”

“…Concomitantly, Tiam1 is recruited, activating the Rac1-PAK-LIMK-Cofilin pathway to provide for spine destabilization and finally cytoskeletal disassembly [ 70 ]. Although the regulatory mechanism remains to be fully explained, it is interesting to notice that both SEMA3B and SEMA3F release is activity-dependent [ 69 , 70 ]. Activity, in turn, induces clustering of adhesion molecules, NRP2 and PLXNAs to the surface of less active spines for their turnover.…”

Doublecortin-like kinase 1 (DCLK1) Facilitates Dendritic Spine Growth of Pyramidal Neurons in Mouse Prefrontal Cortex

“…The L1 family cell adhesion molecules Neuron-glia related protein (NrCAM) and Close Homolog of L1 (CHL1) mediate selective pruning of dendritic spine subpopulations in the mouse neocortex in response to class 3 secreted Semaphorins (Sema3s) through an activity dependent mechanism (Tran et al, 2009;Mohan et al, 2019a;Mohan et al, 2019b). Heterotrimeric receptors comprising L1-CAMs, Neuropilins (Npn1-2), and PlexinAs (PlexA1-4) transduce Sema3 signals to achieve selective spine pruning (Duncan et al, 2021a;Duncan et al, 2021b). All L1-CAMs share a conserved cytoplasmic domain containing the motif FIGQY (FIGAY in CHL1) that binds the actin-spectrin adaptor protein Ankyrin when the tyrosine (Y) residue is not phosphorylated (Bennett and Healy, 2009).…”

The L1 Cell Adhesion Molecule Constrains Dendritic Spine Density through Ankyrin Binding in Pyramidal Neurons of the Mouse Cerebral Cortex

“…Recent studies with L1-CAM-deficient mouse models have revealed novel roles for NrCAM and CHL1 in constraining the density of dendritic spines and excitatory synapses on apical dendrites of cortical pyramidal neurons in the PFC (32-35). Distinct spine subpopulations are pruned in response to secreted Semaphorin-3 ligands Sema3F and Sema3B through receptor complexes comprising NrCAM/Neuropilin2/PlexinA3 and CHL1/Neuropilin2/PlexinA4, respectively.…”