Edinburgh Explorer Heparan sulphate sulphation by Hs2st restricts astroglial precursor somal translocation in developing mouse forebrain by a non cell autonomous mechanism
Edinburgh Explorer Heparan sulphate sulphation by Hs2st restricts astroglial precursor somal translocation in developing mouse forebrain by a non cell autonomous mechanism
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发表时间：
2019
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通讯作者：
James M. Clegg;Hannah M. Parkin;J. Mason;T. Pratt
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作者：
James M. Clegg;Hannah M. Parkin;J. Mason;T. Pratt
硫酸乙酰肝素（HS）是一种细胞表面和细胞外基质碳水化合物，经差异硫酸化作用广泛修饰。HS与通过细胞外信号调节激酶激活激酶（MAPK）途径发出信号的典型成纤维细胞生长因子（FGF）蛋白质物理相互作用。在小鼠中线，FGF/ERK信号传导驱动星形胶质细胞前体体从皮质-间隔边界（CSB）的心室区易位到industrialgriseum（IG），产生表达Slit 2的星形胶质细胞路标细胞的焦点，这些细胞对于半球间胼胝体（CC）轴突导航至关重要。在这里，我们调查的细胞和分子功能的一种特定形式的HS硫酸化，2-O HS硫酸化催化的酶Hs 2st，在中线星形胶质细胞的发展和调节FGF蛋白水平和与HS的相互作用。Hs 2st-/-胚胎的任何性别表现出一个巨大的IG由于早熟的星形胶质细胞易位和条件Hs 2st诱变和离体培养实验表明，Hs 2st是不需要细胞自主CC轴突或IG星形胶质细胞谱系，而是非细胞自主抑制易位信号的传输星形胶质细胞前体。通过抑制FGF信号传导拯救Hs 2st-/-星形胶质细胞易位表型显示Hs 2st的正常作用是抑制FGF介导的星形胶质细胞易位。我们证明了Hs 2st对FGF蛋白的选择性作用，表明Hs 2st（而不是Hs 6st 1）通常抑制体内CSB区域中Fgf 17蛋白的水平，并使用生化测定显示Hs 2st（而不是Hs 6st 1）促进Fgf 17蛋白和HS之间的物理相互作用。细胞自主机制我们进一步表明，Hs 2st修饰57选择性地促进Fgf 17和HS之间的物理相互作用，并抑制体内Fgf 17蛋白58水平，强烈表明Hs 2st选择性地作用于Fgf 17信号传导。HS 59与许多信号蛋白相互作用，可能编码许多在发育和疾病中重要的选择性相互作用，因此这类机制可能更广泛地应用于其他生物系统。
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 activated kinase (MAPK) pathway. At the mouse 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. cell autonomous mechanism. We further show that Hs2st modification 57 selectively facilitates physical interaction between Fgf17 and HS and supresses Fgf17 protein 58 levels in vivo , strongly suggesting that Hs2st acts selectively on Fgf17 signalling. HS 59 interacts with many signalling proteins potentially encoding numerous selective interactions 60 important in development and disease so this class of mechanism may apply more broadly to 61 other biological systems.