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The Journal of Neuroscience, June 28, 2006, 26(26):6911-6923; doi:10.1523/JNEUROSCI.0505-06.2006
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Development/Plasticity/Repair
Heparan Sulphation Patterns Generated by Specific Heparan Sulfotransferase Enzymes Direct Distinct Aspects of Retinal Axon Guidance at the Optic Chiasm
Thomas Pratt, Christopher D. Conway, Natasha M. M.-L. Tian, David J. Price, andJohn O. Mason Genes and Development Group, Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom
Correspondence should be addressed to Dr. Thomas Pratt, Genes and Development Group, Biomedical Sciences, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK. Email: t.pratt{at}ed.ac.uk
Retinal ganglion cell (RGC) axons from each eye execute a series of maneuvers as they converge on the ventral surface of the brain at the optic chiasm for sorting into the optic tracts. Heparan sulfate proteoglycans (HSPGs) are extracellular glycoproteins involved in cell-surface interactions. HSPGs exhibit massive structural diversity, conferred partly by extensive post-translational modification including differential sulfation. Here we examine the roles of HSPG sulfation in RGC axon guidance at the chiasm. We identified different axon navigation phenotypes in two heparan sulfate sulfotransferase (Hst) mutant embryos, Hs2st–/– and Hs6st1–/–, each lacking an enzyme that catalyzes a particular HSPG modification. Hs2st–/– embryos display axon disorganization at the chiasm. Hs6st1–/– embryos exhibit prolific inter-retinal innervation. We show that RGCs express Hs2st and Hs6st1 and that navigation errors made by their axons coincide with regions of high Hs2st and/or Hs6st1 expression at the chiasm. Slit proteins are expressed at particular locations in the retina and around the chiasm and are normally deployed to prevent axons entering inappropriate territories. We show that Hs2st and/or Hs6st1 expression coincides with Slit expression domains at locations where RGC axons make navigation errors in Hs2st–/– and Hs6st1–/– mutants and that Hs6st1–/– RGC axons are less sensitive to Slit2 repulsion than their wild-type counterparts in vitro. We suggest that (1) Hs2st and Hs6st1 are each deployed to generate distinct patterns of heparan sulfation on RGCs and at the optic chiasm and (2) this differential sulfation directs retinal axons through the chiasm, at least in part by modulating the response of the navigating growth cone to Slit proteins.
Key words: Hs2st; Hs6st1; transgenic; mouse; Robo; Slit; retinal ganglion cell; optic chiasm
Received July 15, 2005; revised April 5, 2006; accepted May 6, 2006.
Correspondence should be addressed to Dr. Thomas Pratt, Genes and Development Group, Biomedical Sciences, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK. Email: t.pratt{at}ed.ac.uk
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