Plexin-A4 Mediates Axon-Repulsive Activities of Both Secreted and Transmembrane Semaphorins and Plays Roles in Nerve Fiber Guidance

Abstract

It has been proposed that four members of the plexin A subfamily (plexin-As; plexin-A1, -A2, -A3, and -A4) and two neuropilins (neuropilin-1 and neuropilin-2) form complexes and serve as receptors for class 3 secreted semaphorins (Semas), potent neural chemorepellents. The roles of given plexin-As in semaphorin signaling and axon guidance, however, are mostly unknown. Here, to elucidate functions of plexin-A4 in semaphorin signaling and axon guidance events in vivo, we generated plexin-A4 null mutant mice by targeted disruption of the plexin-A4 gene. Plexin-A4 mutant mice were defective in the trajectory and projection of peripheral sensory axons and sympathetic ganglion (SG) axons and the formation of the anterior commissure and the barrels. The defects in peripheral sensory and SG axons were fundamentally related to those of neuropilin-1 or Sema3A mutant embryos reported but were more moderate than the phenotype in these mutants. The growth cone collapse assay showed that dorsal root ganglion axons and SG axons of plexin-A4 mutant embryos partially lost their responsiveness to Sema3A. These results suggest that plexin-A4 plays roles in the propagation of Sema3A activities and regulation of axon guidance and that other members of the plexin-A subfamily are also involved in the propagation of Sema3A activities. Plexin-A4-deficient SG axons did not lose their responsiveness to Sema3F, suggesting that plexin-A4 serves as a Sema3A-specific receptor, at least in SG axons. In addition, the present study showed that plexin-A4 bound class 6 transmembrane semaphorins, Sema6A and Sema6B, and mediated their axon-repulsive activities, independently of neuropilin-1. Our results imply that plexin-A4 mediates multiple semaphorin signals and regulates axon guidance in vivo.

Identification of Candidate Genes for Alcohol Preference by Expression Profiling of Congenic Rat Strains

“…Plxna4 mediates multiple semaphorin signals, which are important in the development of the nervous system (Suto et al, 2005), and plays roles in a wide variety of axon guidance events in a highly regulated manner (Ben-Zvi et al, 2006). The protein Scap2 is an src-kinase associated protein.…”

MICAL flavoprotein monooxygenases: Expression during neural development and following spinal cord injuries in the rat

“…The specific responses of different classes of neurons to individual Sema3s can be explained in part by restricted and unique neuropilin distribution patterns and by the preferential binding of individual Sema3s to neuropilin-1 and/or neuropilin-2 (Chen et al, 1997(Chen et al, , 1998Feiner et al, 1997;Giger et al, 1998Giger et al, , 2000He and Tessier-Lavigne, 1997;Kolodkin et al, 1997). In addition, individual plexinAs also contribute to the specificity of axonal responses to Sema3s (Cheng et al, 2001;Suto et al, 2005;Yaron et al, 2005). How plexinAs discriminate between different Sema3s and transduce Sema3-specific signals is still unclear.…”

ADAM metalloproteases promote a developmental switch in responsiveness to the axonal repellant Sema3A

“…The receptor complex for the axonal repellant Semaphorin3A (Sema3A) comprises two core elements: Neuropilin-1 (Nrp1), which binds the ligand but lacks signalling capabilities [25][26][27] , and type-A Plexin, which transmits the signal 28,29 . Two other components implicated in activation of the response to Sema3A and endocytosis of the receptor complex, respectively, are the L1 cell adhesion molecule (L1-CAM) and the transiently expressed axonal glycoprotein-1 (TAG-1) [30][31][32][33] .…”