title: Specific modification of heparan sulphate is required for normal cerebral cortical development.
abstract: Proteoglycans are cell surface and extracellular matrix molecules to which long, unbranched glycosaminoglycan side chains are attached. Heparan sulphate, a type of glycosaminoglycan chain, has been proposed as a co-factor necessary for signalling by a range of growth factors. Here we provide evidence that loss of 2-O-sulphation in heparan sulphate leads to a significant reduction in cell proliferation in the developing cerebral cortex. The gene encoding heparan sulphate 2-sulphotransferase (Hs2st) is expressed in embryonic cortex and histological analysis of mice homozygous for a null mutation in Hs2st indicated a reduction in the thickness of the embryonic cerebral cortex. Using 5'-bromodeoxyuridine (BrdU) incorporation assays we found a reduction of approximately 40% in labelling indices of cortical precursor cells at E12. Comparison of the fates of cortical cells born on E13 and E15 in Hs2st(-/-) mutant and wildtype littermate embryos revealed no differences in the pattern of cell migration. Our findings suggest a critical role for 2-O-sulphation of heparan sulphate proteoglycan (HSPG) in regulating cell proliferation during development of the cerebral cortex, perhaps through the modulation of cellular responses to growth factor signalling.
authors.affiliation: Division of Biomedical Sciences, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors.forename: David
authors.initials: D
authors.lastname: McLaughlin
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karlsson
authors.forename: Natasha
authors.initials: N
authors.lastname: Tian
authors.forename: Thomas
authors.initials: T
authors.lastname: Pratt
authors.forename: Simon L
authors.initials: SL
authors.lastname: Bullock
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Wilson
authors.forename: David J
authors.initials: DJ
authors.lastname: Price
authors.forename: John O
authors.initials: JO
authors.lastname: Mason
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine; D002455:Cell Division; D002465:Cell Movement; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000201:enzymology / Q000378:metabolism*; D017353:Gene Deletion; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013431:Sulfates / Q000378:metabolism; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D001973:Bromodeoxyuridine; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D013431:Sulfates; D015238:Sulfotransferases; C106358:heparan-sulfate 2-sulfotransferase