title: Role of heparan sulfate proteoglycans in optic disc and stalk morphogenesis.
abstract: BACKGROUND
  Heparan sulfate proteoglycans (HSPG) are important for embryonic development by means of the regulation of gradient formation and signaling of multiple growth factors and morphogens. Previous studies have shown that Bmp/Shh/Fgf signaling are required for the regionalization of the optic vesicle (OV) and for the closure of the optic fissure (OF), the disturbance of which underlie ocular anomalies such as microphthalmia, coloboma, and optic nerve hypoplasia.
  
  
  RESULTS
  To study HSPG-dependent coordination of these signaling pathways during mammalian visual system development, we have generated a series of OV-specific mutations in the heparan sulfate (HS) N-sulfotransferase genes (Ndst1 and Ndst2) and HS O-sulfotransferase genes (Hs2st, Hs6st1, and Hs6st2) in mice. Of interest, the resulting HS undersulfation still allowed for normal retinal neurogenesis and optic fissure closure, but led to defective optic disc and stalk development. The adult mutant animals further developed optic nerve aplasia/hypoplasia and displayed retinal degeneration. We observed that MAPK/ERK signaling was down-regulated in Ndst mutants, and consistent with this, HS-related optic nerve morphogenesis defects in mutant mice could partially be rescued by constitutive Kras activation.
  
  
  CONCLUSIONS
  These results suggest that HSPGs, depending on their HS sulfation pattern, regulate multiple signaling pathways in optic disc and stalk morphogenesis.
authors.affiliation: Department of Ophthalmology, Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Cai
authors.forename: Kay
authors.initials: K
authors.lastname: Grobe
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000581:Amidohydrolases / Q000235:genetics; D000818:Animals; D004622:Embryo, Mammalian; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics; D009898:Optic Disk / Q000196:embryology* / Q000378:metabolism; D009901:Optic Nerve Diseases / Q000235:genetics; D065866:Optic Tract / Q000196:embryology* / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015238:Sulfotransferases / Q000235:genetics
chemical_list: D019812:Heparan Sulfate Proteoglycans; C485756:Hs6st1 protein, mouse; C485758:Hs6st2 protein, mouse; C491855:Ndst2 protein, mouse; D015238:Sulfotransferases; C106358:heparan-sulfate 2-sulfotransferase; C021350:heparitin sulfotransferase; D000581:Amidohydrolases
keywords: Fgf; HSPG; Ndst; optic disc; optic stalk; sulfotransferase
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