Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans.
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.
Kantor
David B
DB
Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
Chivatakarn
Onanong
O
Peer
Katherine L
KL
Oster
Stephen F
SF
Inatani
Masaru
M
Hansen
Michael J
MJ
Flanagan
John G
JG
Yamaguchi
Yu
Y
Sretavan
David W
DW
Giger
Roman J
RJ
Kolodkin
Alex L
AL
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
D011508:Chondroitin Sulfate Proteoglycans; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C103619:Sema5A protein, mouse; D039961:Semaphorins