title: Sulf1 and Sulf2 Differentially Modulate Heparan Sulfate Proteoglycan Sulfation during Postnatal Cerebellum Development: Evidence for Neuroprotective and Neurite Outgrowth Promoting Functions.
abstract: BACKGROUND
  Sulf1 and Sulf2 are cell surface sulfatases, which remove specific 6-O-sulfate groups from heparan sulfate (HS) proteoglycans, resulting in modulation of various HS-dependent signaling pathways. Both Sulf1 and Sulf2 knockout mice show impairments in brain development and neurite outgrowth deficits in neurons.
  
  
  RESULTS
  To analyze the molecular mechanisms behind these impairments we focused on the postnatal cerebellum, whose development is mainly characterized by proliferation, migration, and neurite outgrowth processes of precursor neurons. Primary cerebellar granule cells isolated from Sulf1 or Sulf2 deficient newborns are characterized by a reduction in neurite length and cell survival. Furthermore, Sulf1 deficiency leads to a reduced migration capacity. The observed impairments in cell survival and neurite outgrowth could be correlated to Sulf-specific interference with signaling pathways, as shown for FGF2, GDNF and NGF. In contrast, signaling of Shh, which determines the laminar organization of the cerebellar cortex, was not influenced in either Sulf1 or Sulf2 knockouts. Biochemical analysis of cerebellar HS demonstrated, for the first time in vivo, Sulf-specific changes of 6-O-, 2-O- and N-sulfation in the knockouts. Changes of a particular HS epitope were found on the surface of Sulf2-deficient cerebellar neurons. This epitope showed a restricted localization to the inner half of the external granular layer of the postnatal cerebellum, where precursor cells undergo final maturation to form synaptic contacts.
  
  
  CONCLUSIONS
  Sulfs introduce dynamic changes in HS proteoglycan sulfation patterns of the postnatal cerebellum, thereby orchestrating fundamental mechanisms underlying brain development.
authors.affiliation: Fakultät für Chemie, Biochemie I, Universität Bielefeld, Bielefeld, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Kalus
authors.affiliation: Fakultät für Chemie, Biochemie I, Universität Bielefeld, Bielefeld, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Rohn
authors.affiliation: Centre for Glycobiology, School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Tania M
authors.initials: TM
authors.lastname: Puvirajesinghe
authors.affiliation: Centre for Glycobiology, School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Guimond
authors.affiliation: Fakultät für Chemie, Biochemie I, Universität Bielefeld, Bielefeld, Germany.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Eyckerman-Kölln
authors.affiliation: Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands, Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegan, The Netherlands.
authors.forename: Gerdy
authors.initials: G
authors.lastname: Ten Dam
authors.affiliation: Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands, Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegan, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Centre for Glycobiology, School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Turnbull
authors.affiliation: Fakultät für Chemie, Biochemie I, Universität Bielefeld, Bielefeld, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dierks
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000494:pharmacology; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction; D013429:Sulfatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans; C465570:Shh protein, mouse; D016222:Fibroblast Growth Factor 2; D020932:Nerve Growth Factor; C486773:Sulf1 protein, mouse; D015238:Sulfotransferases; C514911:Sulf2 protein, mouse; D013429:Sulfatases