title: Heparan sulfate sugar modifications mediate the functions of slits and other factors needed for mouse forebrain commissure development.
abstract: Heparan sulfate proteoglycans are cell surface and secretory proteins that modulate intercellular signaling pathways including Slit/Robo and FGF/FGFR. The heparan sulfate sugar moieties on HSPGs are subject to extensive postsynthetic modification, generating enormous molecular complexity that has been postulated to provide increased diversity in the ability of individual cells to respond to specific signaling molecules. This diversity could help explain how a relatively small number of axon guidance molecules are able to instruct the extremely complex connectivity of the mammalian brain. Consistent with this hypothesis, we previously showed that mutant mice lacking the heparan sulfotransferases (Hsts) Hs2st or Hs6st1 display major axon guidance defects at the developing optic chiasm. Here we further explore the role of these Hsts at the optic chiasm and investigate their function in corpus callosum development. Each Hst is expressed in a distinct pattern and each mutant displays a specific spectrum of axon guidance defects. Particular Hs2st(-/-) and Hs6st1(-/-) phenotypes closely match those of Slit1(-/-) and Slit2(-/-) embryos respectively, suggesting possible functional relationships. To test functional interactions between Hs2st or Hs6st1 and Slits we examined optic chiasm and corpus callosum phenotypes in a panel of genotypes where Hs2st or Hs6st1 and Slit1 or Slit2 function were simultaneously reduced or absent. We find examples of Hs2st and Hs6st1 having epistatic, synergistic, and antagonistic genetic relationships with Slit1 and/or Slit2 depending on the context. At the corpus callosum we find that Hs6st1 has Slit-independent functions and our data indicate additional roles in FGF signaling.
authors.affiliation: Genes and Development Group, Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Conway
authors.forename: Kathy M
authors.initials: KM
authors.lastname: Howe
authors.forename: Nicole K
authors.initials: NK
authors.lastname: Nettleton
authors.forename: David J
authors.initials: DJ
authors.lastname: Price
authors.forename: John O
authors.initials: JO
authors.lastname: Mason
authors.forename: Thomas
authors.initials: T
authors.lastname: Pratt
mesh_terms: D000596:Amino Acids; D000818:Animals; D019521:Body Patterning / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D003337:Corpus Callosum / Q000196:embryology; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D009897:Optic Chiasm / Q000196:embryology / Q000201:enzymology; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology* / Q000201:enzymology; D012160:Retina / Q000166:cytology / Q000196:embryology; D012165:Retinal Ganglion Cells / Q000378:metabolism; D015238:Sulfotransferases / Q000172:deficiency / Q000378:metabolism*; D014795:Visual Pathways / Q000196:embryology / Q000378:metabolism; D000098552:Slit Homolog 2 Protein
chemical_list: D000596:Amino Acids; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C120010:Slit1 protein, mouse; C098463:dolaisoleucine; C485756:Hs6st1 protein, mouse; D015238:Sulfotransferases; C106358:heparan-sulfate 2-sulfotransferase; D000098552:Slit Homolog 2 Protein