title: Distinct cytoplasmic domains in Plexin-A4 mediate diverse responses to semaphorin 3A in developing mammalian neurons.
abstract: Guidance receptor signaling is crucial for neural circuit formation and elicits diverse cellular events in specific neurons. We found that signaling from the guidance cue semaphorin 3A diverged through distinct cytoplasmic domains in its receptor Plexin-A4 to promote disparate cellular behavior in different neuronal cell types. Plexin-A4 has three main cytoplasmic domains--C1, Hinge/RBD, and C2--and interacts with family members of the Rho guanine nucleotide exchange factor FARP proteins. We show that growth cone collapse occurred in Plexin-A4-deficient dorsal root ganglion sensory neurons reconstituted with Plexin-A4 containing either the Hinge/RBD or C2 domain, whereas both of the Hinge/RBD and C1 domains were required for dendritic arborization in cortical neurons. Although knockdown studies indicated that both the collapse and arborization responses involved FARP2, mutations in the cytoplasmic region of Plexin-A4 that reduced its interaction with FARP2 strongly inhibited semaphorin 3A-induced dendritic branching but not growth cone collapse, suggesting that different degrees of interaction are required for the two responses or that developing axons have an indirect path to FARP2 activation. Thus, our study provided insights into the multifunctionality of guidance receptors, in particular showing that the semaphorin 3A signal diverges through specific functions of the modular domains of Plexin-A4.
authors.affiliation: 1Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Guy
authors.initials: G
authors.lastname: Mlechkovich
authors.forename: Sheng-Shiang
authors.initials: SS
authors.lastname: Peng
authors.forename: Vered
authors.initials: V
authors.lastname: Shacham
authors.forename: Edward
authors.initials: E
authors.lastname: Martinez
authors.forename: Irena
authors.initials: I
authors.lastname: Gokhman
authors.forename: Adi
authors.initials: A
authors.lastname: Minis
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Tran
authors.forename: Avraham
authors.initials: A
authors.lastname: Yaron
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology; D020439:Growth Cones / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D040121:Semaphorin-3A / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C507259:FARP2 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; C492110:Plxna4 protein, mouse; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A