Regulation of dendritic development by semaphorin 3A through novel intracellular remote signaling

Abstract

Numerous cell adhesion molecules, extracellular matrix proteins and axon guidance molecules participate in neuronal network formation through local effects at axo-dendritic, axo-axonic or dendro-dendritic contact sites. In contrast, neurotrophins and their receptors play crucial roles in neural wiring by sending retrograde signals to remote cell bodies. Semaphorin 3A (Sema3A), a prototype of secreted type 3 semaphorins, is implicated in axon repulsion, dendritic branching and synapse formation via binding protein neuropilin-1 (NRP1) and the signal transducing protein PlexinAs (PlexAs) complex. This review focuses on Sema3A retrograde signaling that regulates dendritic localization of AMPA-type glutamate receptor GluA2 and dendritic patterning. This signaling is elicited by activation of NRP1 in growth cones and is propagated to cell bodies by dynein-dependent retrograde axonal transport of PlexAs. It also requires interaction between PlexAs and a high-affinity receptor for nerve growth factor, toropomyosin receptor kinase A. We propose a control mechanism by which retrograde Sema3A signaling regulates the glutamate receptor localization through trafficking of cis-interacting PlexAs with GluA2 along dendrites; this remote signaling may be an alternative mechanism to local adhesive contacts for neural network formation.

Keywords: CRMPs; axonal transport; dendritic branching; neurotrophins; semaphorins; spine maturation.

Figure 1.

Signaling model of Sema3A. The plexin RasGAP inactivates ligand-binding–induced R-Ras inactivation. PlexinA GAP activity is regulated by FERM, RhoGEF and pleckstrin domain protein 2 (FARP2)-mediated Rac1 activation. After Sema3A stimulation, FARP2 dissociates from plexinA1 and activates Rac1 in neuronal growth cones. Active Rac1 facilitates the association of Rnd1, a small GTPase, with PlexA1 and may modulate actin dynamics through the sequential activation of p21-activated kinase, LIM kinase 1 and coffilin. Rnd1-PlexAs interactions stimulate PlexAs GAP activity toward R-Ras by releasing or terminating inhibitory interactions within the plexin cytoplasmic region. Plexin-induced inhibition of PI3K-Akt signaling prevents the inactivation of the serine/2hreonine kinase glycogen synthase kinase-3β (GSK-3β), thus promoting the phosphorylation and inactivation of CRMP2. Sema3A also activates Src type tyrosine kinase Fyn, thereby leading to sequential phosphorylation of CRMP2 by Cdk5 and GSK3β to regulate axon guidance and dendritic development. Cdk5 phosphorylates CRMP1 and CRMP2 at Ser522, and GSK3β subsequently phosphorylates Thr509 and Thr514 of CRMP2.

Figure 2.

A model for retrograde Sema3A signaling that drives AMPA receptor subunit GluA2 to dendrites. After activation of receptor complex for Sema3A, Ca²⁺ channels and ryanodine receptors are activated, which trigger intracellular Ca²⁺ mobilization, which subsequently induce clathrin-dependent endocytosis of the receptor complex Sema3A/2lexA4/2RP1/2rkA in the growth cone. The transport may be coupled with intracellular Ca²⁺ channels as well as voltage-dependent Ca²⁺ and Na⁺ channels at the plasma membrane. The Sema3A/2lexA4/2RP1/2rkA complex is then transported through interaction between PlexA4, TrkA and dynein motor protein toward the somatodendritic region. PlexA4 interacts with GluA2 through its extracellular IPT-domain in the somatodendritic region, then escorts it to the distal dendrites.

Figure 3.

Crosstalk between Sema3A and NGF. The axonal growth cone as a site of Sema3A action responsible for dendritic localization of GluA2 at an early embryonic stage. The site of action may also localize in the somatodendritic regions, especially in mature neurons possessing a long axon and multiple dendrites. Determining neurite extension or retraction and cell survival or death might depend on the balance between the levels of NGF and Sema3A signaling that are initiated.