The RacGAP β2-Chimaerin Selectively Mediates Axonal Pruning in the Hippocampus

• Published in: Cell Vol. 149; no. 7; pp. 1594 - 1606
• Main Authors: Riccomagno, Martin M., Hurtado, Andrés, Wang, HongBin, Macopson, Joshua G.J., Griner, Erin M., Betz, Andrea, Brose, Nils, Kazanietz, Marcelo G., Kolodkin, Alex L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.06.2012
• Subjects: Animals; axons; Axons - metabolism; cytoskeleton; Dentate Gyrus - metabolism; GTPase-activating proteins; hippocampus; Hippocampus - cytology; Hippocampus - metabolism; Humans; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Neoplasm Proteins - metabolism; Nerve Tissue Proteins - metabolism; Neurons - metabolism; Neuropeptides - metabolism; pruning; rac GTP-Binding Proteins - metabolism; rac1 GTP-Binding Protein; Signal Transduction; synapse; Synapses
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.05.018

Axon pruning and synapse elimination promote neural connectivity and synaptic plasticity. Stereotyped pruning of axons that originate in the hippocampal dentate gyrus (DG) and extend along the infrapyramidal tract (IPT) occurs during postnatal murine development by neurite retraction and resembles axon repulsion. The chemorepellent Sema3F is required for IPT axon pruning, dendritic spine remodeling, and repulsion of DG axons. The signaling events that regulate IPT axon pruning are not known. We find that inhibition of the small G protein Rac1 by the Rac GTPase-activating protein (GAP) β2-Chimaerin (β2Chn) mediates Sema3F-dependent pruning. The Sema3F receptor neuropilin-2 selectively binds β2Chn, and ligand engagement activates this GAP to ultimately restrain Rac1-dependent effects on cytoskeletal reorganization. β2Chn is necessary for axon pruning both in vitro and in vivo, but it is dispensable for axon repulsion and spine remodeling. Therefore, a Npn2/β2Chn/Rac1 signaling axis distinguishes DG axon pruning from the effects of Sema3F on repulsion and dendritic spine remodeling. [Display omitted] ► Sema3F downregulates RacGTP levels in hippocampal neurons ► Sema3F activation of the RacGAP β2Chn promotes synaptic pruning ► β2Chn is not required for Sema3F-mediated axon repulsion or constraint of spines ► β2Chn and its GAP activity are required for dentate gyrus IPT axonal pruning Binding of Sema3F to its receptor promotes three distinct neuronal behaviors: axon pruning, dendritic spine remodeling, and axon repulsion. Identifying a RacGAP that acts downstream of the Sema3F receptor to specifically mediate Sema3F-dependent axon pruning provides insight into how actin regulators can be differentially deployed downstream of the same ligand-receptor interaction.