Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans

Neuron. 2004 Dec 16;44(6):961-75. doi: 10.1016/j.neuron.2004.12.002.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Axons / metabolism*
  • Cell Line
  • Chondroitin Sulfate Proteoglycans / genetics
  • Chondroitin Sulfate Proteoglycans / physiology*
  • Dose-Response Relationship, Drug
  • Female
  • Heparan Sulfate Proteoglycans / genetics
  • Heparan Sulfate Proteoglycans / physiology*
  • Humans
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mesencephalon / embryology
  • Mesencephalon / metabolism
  • Mice
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Organ Culture Techniques
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Semaphorins


  • Chondroitin Sulfate Proteoglycans
  • Heparan Sulfate Proteoglycans
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Sema5A protein, mouse
  • Semaphorins