Heparan sulphate proteoglycans and spinal neurulation in the mouse embryo.
Heparan sulphate proteoglycans have been implicated in the binding and presentation of several growth factors to their receptors, thereby regulating cellular growth and differentiation. To investigate the role of heparan sulphate proteoglycans in mouse spinal neurulation, we administered chlorate, a competitive inhibitor of glycosaminoglycan sulphation, to cultured E8.5 embryos. Treated embryos exhibit accelerated posterior neuropore closure, accompanied by suppression of neuroepithelial bending at the median hinge point and accentuated bending at the paired dorsolateral hinge points of the posterior neuropore. These effects appear specific, as they can be prevented by addition of heparan sulphate to the culture medium, whereas heparitinase-treated heparan sulphate and chondroitin sulphate are ineffective. Both N- and O-sulphate groups appear to be necessary for the action of heparan sulphate. In situ hybridisation analysis demonstrates a normal distribution of sonic hedgehog mRNA in chlorate-treated embryos. By contrast, patched 1 transcripts are abnormally abundant in the notochord, and diminished in the overlying neuroepithelium, suggesting that sonic hedgehog signalling from the notochord may be perturbed by inhibition of heparan sulphation. Together, these results demonstrate a regulatory role for heparan sulphate in mouse spinal neurulation.
Yip
George W
GW
Developmental Biology Unit, Institute of Child Health, University College London, London, UK.
Ferretti
Patrizia
P
Copp
Andrew J
AJ
D000199:Actins / Q000378:metabolism; D000818:Animals; D002704:Chlorates / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000378:metabolism; D006027:Glycosides / Q000494:pharmacology; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000196:embryology*; D013431:Sulfates / Q000737:chemistry; D015534:Trans-Activators / Q000235:genetics
D000199:Actins; D002704:Chlorates; D006025:Glycosaminoglycans; D006027:Glycosides; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D013431:Sulfates; D015534:Trans-Activators; C010807:xylosides