Axonal heparan sulfate proteoglycans regulate the distribution and efficiency of the repellent slit during midline axon guidance

Karl G. Johnson, Aurnab Ghose, Elizabeth Epstein, John Lincecum, Michael B. O'Connor, David Van Vactor

Research output: Contribution to journalArticlepeer-review

157 Scopus citations

Abstract

The presentation of secreted axon guidance factors plays a major role in shaping central nervous system (CNS) connectivity [1]. 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 [2-4]. 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.

Original languageEnglish (US)
Pages (from-to)499-504
Number of pages6
JournalCurrent Biology
Volume14
Issue number6
DOIs
StatePublished - Mar 23 2004

Bibliographical note

Funding Information:
We would like to thank Gyeong-Hun Baeg, Norbert Perrimon, and Stefan Thor for Drosophila stocks. We thank our colleagues Mark Emerson and Bharatkumar Patel for invaluable assistance and insight. We would also like to thank Jennifer Waters-Schuler at the Nikon Imaging Center at Harvard Medical School for assistance with confocal microscopy and Norbert Perrimon for critical comments on the manuscript. We are very grateful to Dr. T. Uemura for anti-N-Cadherin antibodies. We also thank the Developmental Studies Hybridoma Bank (DSHB) for its repository of available antibodies; the DSHB was developed under the auspices of the National Institute of Child Health and Development and maintained by the University of Iowa, Department of Biological Sciences. D.V.V. is a Leukemia and Lymphoma Society Scholar and is supported by grants from the National Institute of Neurological Disease and Stroke (NS35909 and NS40043). M.B.O. is supported by funds from the Howard Hughes Medical Institute, and K.G. J. is supported by a postdoctoral fellowship from the Helen Hay Whitney foundation.

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