Axonal heparan sulfate proteoglycans regulate the distribution and efficiency of the repellent slit during midline axon guidance.
The presentation of secreted axon guidance factors plays a major role in shaping central nervous system (CNS) connectivity. Recent work suggests that heparan sulfate (HS) regulates guidance factor activity; however, the in vivo axon guidance roles of its carrier proteins (heparan sulfate proteoglycans, or HSPGs) are largely unknown. Here we demonstrate through genetic analysis in vivo that the HSPG Syndecan (Sdc) is critical for the fidelity of Slit repellent signaling at the midline of the Drosophila CNS, consistent with the localization of Sdc to CNS axons. sdc mutants exhibit consistent defects in midline axon guidance, plus potent and specific genetic interactions supporting a model in which HSPGs improve the efficiency of Slit localization and/or signaling. To test this hypothesis, we show that Slit distribution is altered in sdc mutants and that Slit and its receptor bind to Sdc. However, when we compare the function of the transmembrane Sdc to a different class of HSPG that localizes to CNS axons (Dallylike), we find functional redundancy, suggesting that these proteoglycans act as spatially specific carriers of common HS structures that enable growth cones to interact with and perceive Slit as it diffuses away from its source at the CNS midline.
Johnson
Karl G
KG
Harvard Medical School, Department of Cell Biology, Program in Neuroscience, 240 Longwood Avenue, Boston, MA 02115, USA.
Ghose
Aurnab
A
Epstein
Elizabeth
E
Lincecum
John
J
O'Connor
Michael B
MB
Van Vactor
David
D
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D002490:Central Nervous System / Q000196:embryology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008959:Models, Neurological; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011233:Precipitin Tests; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053667:Syndecans
D029721:Drosophila Proteins; D006497:Heparan Sulfate; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011509:Proteoglycans; D053667:Syndecans; C420997:dlp protein, Drosophila; C066819:sli protein, Drosophila