Projects per year
Heparan sulphate (HS) is a cell surface and extracellular matrix carbohydrate extensively modified by differential sulphation. HS interacts physically with canonical fibroblast growth factor (FGF) proteins that signal through the extracellular signal regulated kinase (ERK)/mitogen activated kinase (MAPK) pathway. At the embryonic mouse telencephalic midline FGF/ERK signalling drives astroglial precursor somal translocation from the ventricular zone of the cortico-septal boundary (CSB) to the induseum griseum (IG) producing a focus of Slit2-expressing astroglial guidepost cells essential for inter-hemispheric corpus callosum (CC) axon navigation. Here we investigate the cell and molecular function of a specific form of HS sulphation, 2-O HS sulphation catalysed by the enzyme Hs2st, in midline astroglial development and in regulating FGF protein levels and interaction with HS. Hs2st-/- embryos of either sex exhibit a grossly enlarged IG due to precocious astroglial translocation and conditional Hs2st mutagenesis and ex vivo culture experiments show that Hs2st is not required cell autonomously by CC axons or by the IG astroglial cell lineage but rather acts non cell autonomously to suppress the transmission of translocation signals to astroglial precursors. Rescue of the Hs2st-/- astroglial translocation phenotype by pharmacologically inhibiting FGF signalling shows the normal role of Hs2st is to suppress FGF-mediated astroglial translocation. We demonstrate a selective action of Hs2st on FGF protein by showing that Hs2st (but not Hs6st1) normally suppresses the levels of Fgf17 protein in the CSB region in vivo and use a biochemical assay to show Hs2st (but not Hs6st1) facilitates physical interaction between Fgf17 protein and HS.
How does differential heparin sulphate sulphation instruct fibroblast growth factor signalling in the developing brain
13/06/15 → 12/06/18
Cell and molecular functions of a regulated heparan sulphate structure in the developing corpus callosum
13/01/12 → 12/06/15