Ford-Perriss Miriam, Guimond Scott E, Greferath Una, Kita Magdalena, Grobe Kay, Habuchi Hiroko, Kimata Koji, Esko Jeffrey D, Murphy Mark, Turnbull Jeremy E
Department of Anatomy and Cell Biology, University of Melbourne, Victoria, Australia, 3052.
Glycobiology. 2002 Nov;12(11):721-7. doi: 10.1093/glycob/cwf072.
Heparan sulfates (HSs) exert critical regulatory actions on many proteins, including growth factors, and are essential for normal development. Variations in their specific sulfation patterns are known to regulate binding and signaling of fibroblast growth factors (FGFs) via tyrosine kinase receptors (FGFRs). We previously reported differences in sulfation patterns between HS species expressed by embryonic day 10 (E10) and E12 mouse neural precursor cells. We have examined the abilities of the different HS species to support signaling of the relevant FGF-FGFR combinations expressed early during brain development. For FGF8, which only functions early (E8-E11), E10 HS showed preferential activation. The most potent signaling for FGF8 was via FGFR3c, for which E10 HS was strongly active and E12 HS had no activity. For FGF2, which functions from E10 to E13, HS from both stages showed similar activity and were more potent at activating FGFR1c than the other receptors. Thus, we find a stage-specific correlation with activation. To explore the potential mechanisms for the generation of these stage-specific HS species, we investigated the expression of the HS sulfotransferase (HSST) isozymes responsible for creating diverse sulfation motifs in HS chains. We find that there are stage-specific combinations of HSST isozymes that could underlie the synthesis of different HS species at E10 and E12. Collectively, these data lead us to propose a model in which differential expression of HSSTs results in the synthesis of variant HS species that form functional signaling complexes with FGFs and FGFRs and orchestrate proliferation and differentiation in the developing brain.
硫酸乙酰肝素（HSs）对包括生长因子在内的许多蛋白质发挥关键的调节作用，对正常发育至关重要。已知其特定硫酸化模式的变化可通过酪氨酸激酶受体（FGFRs）调节成纤维细胞生长因子（FGFs）的结合和信号传导。我们之前报道了胚胎第10天（E10）和E12天小鼠神经前体细胞表达的HS种类之间硫酸化模式的差异。我们研究了不同HS种类支持脑发育早期表达的相关FGF-FGFR组合信号传导的能力。对于仅在早期（E8-E11）起作用的FGF8，E10 HS表现出优先激活。FGF8最有效的信号传导是通过FGFR3c，对于该受体，E10 HS具有强烈活性，而E12 HS没有活性。对于在E10至E13起作用的FGF2，两个阶段的HS表现出相似的活性，并且在激活FGFR1c方面比其他受体更有效。因此，我们发现了与激活的阶段特异性相关性。为了探索产生这些阶段特异性HS种类的潜在机制，我们研究了负责在HS链中产生不同硫酸化基序的HS硫酸转移酶（HSST）同工酶的表达。我们发现存在HSST同工酶的阶段特异性组合，这可能是E10和E12不同HS种类合成的基础。总体而言，这些数据使我们提出一个模型，其中HSSTs的差异表达导致变体HS种类的合成，这些变体与FGFs和FGFRs形成功能性信号复合物，并协调发育中大脑的增殖和分化。
