title: Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans.
abstract: The response of neuronal growth cones to axon guidance cues depends on the developmental context in which these cues are encountered. We show here that the transmembrane protein semaphorin 5A (Sema5A) is a bifunctional guidance cue exerting both attractive and inhibitory effects on developing axons of the fasciculus retroflexus, a diencephalon fiber tract associated with limbic function. The thrombospondin repeats of Sema5A physically interact with the glycosaminoglycan portion of both chondroitin sulfate proteoglycans (CSPGs) and heparan sulfate proteoglycans (HSPGs). CSPGs function as precisely localized extrinsic cues that convert Sema5A from an attractive to an inhibitory guidance cue. Therefore, glycosaminoglycan bound guidance cues provide a molecular mechanism for CSPG-mediated inhibition of axonal extension. Further, axonal HSPGs are required for Sema5A-mediated attraction, suggesting that HSPGs are components of functional Sema5A receptors. Thus, neuronal responses to Sema5A are proteoglycan dependent and interpreted according to the biological context in which this membrane bound guidance cue is presented.
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Kantor
authors.forename: Onanong
authors.initials: O
authors.lastname: Chivatakarn
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Peer
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Oster
authors.forename: Masaru
authors.initials: M
authors.lastname: Inatani
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hansen
authors.forename: John G
authors.initials: JG
authors.lastname: Flanagan
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: David W
authors.initials: DW
authors.lastname: Sretavan
authors.forename: Roman J
authors.initials: RJ
authors.lastname: Giger
authors.forename: Alex L
authors.initials: AL
authors.lastname: Kolodkin
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002460:Cell Line; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D008636:Mesencephalon / Q000196:embryology / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D039961:Semaphorins
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C103619:Sema5A protein, mouse; D039961:Semaphorins