Heparan sulphation patterns generated by specific heparan sulfotransferase enzymes direct distinct aspects of retinal axon guidance at the optic chiasm
Heparan sulphation patterns generated by specific heparan sulfotransferase enzymes direct distinct aspects of retinal axon guidance at the optic chiasm
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DOI：
10.1523/jneurosci.0505-06.2006
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发表时间：
2006-06-28
影响因子：
5.3
通讯作者：
Mason, John O.
中科院分区：
文献类型：
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作者：
Pratt, Thomas;Conway, Christopher D.;Mason, John O.
每只眼睛的视网膜神经节细胞 (RGC) 轴突在视交叉处汇聚到大脑腹侧表面以分类到视束时执行一系列操作。硫酸乙酰肝素蛋白聚糖 (HSPG) 是参与细胞表面相互作用的细胞外糖蛋白。 HSPG 表现出巨大的结构多样性，部分是由广泛的翻译后修饰（包括差异硫酸化）赋予的。在这里，我们研究了 HSPG 硫酸化在交叉处 RGC 轴突引导中的作用。我们在两个硫酸乙酰肝素磺基转移酶 (Hst) 突变体胚胎 Hs2st(-/-) 和 Hs6st1(-/-) 中鉴定出不同的轴突导航表型，每个胚胎都缺乏催化特定 HSPG 修饰的酶。 Hs2st(-/-) 胚胎在交叉处显示轴突紊乱。 Hs6st1(-/-) 胚胎表现出丰富的视网膜间神经支配。我们发现 RGC 表达 Hs2st 和 Hs6st1，并且其轴突产生的导航误差与交叉处 Hs2st 和/或 Hs6st1 高表达的区域一致。狭缝蛋白在视网膜和交叉周围的特定位置表达，通常用于防止轴突进入不适当的区域。我们发现，在 Hs2st(-/-) 和 Hs6st1(-/-) 突变体中，Hs2st 和/或 Hs6st1 表达与 RGC 轴突发生导航错误的位置处的 Slit 表达域一致，并且在体外，Hs6st1(-/-) RGC 轴突对 Slit2 排斥的敏感性低于野生型对应物。我们建议（1）Hs2st和Hs6st1各自被部署以在RGC和视交叉处产生不同的乙酰肝素硫酸化模式，（2）这种差异硫酸化至少部分通过调节导航生长锥对狭缝蛋白的反应来引导视网膜轴突穿过交叉。
Retinal ganglion cell (RGC) axons from each eye execute a series of maneuvers as they converge on the ventral surface of the brain at the optic chiasm for sorting into the optic tracts. Heparan sulfate proteoglycans (HSPGs) are extracellular glycoproteins involved in cell-surface interactions. HSPGs exhibit massive structural diversity, conferred partly by extensive post-translational modification including differential sulfation. Here we examine the roles of HSPG sulfation in RGC axon guidance at the chiasm. We identified different axon navigation phenotypes in two heparan sulfate sulfotransferase (Hst) mutant embryos, Hs2st(-/-) and Hs6st1(-/-), each lacking an enzyme that catalyzes a particular HSPG modification. Hs2st(-/-) embryos display axon disorganization at the chiasm. Hs6st1(-/-) embryos exhibit prolific inter-retinal innervation. We show that RGCs express Hs2st and Hs6st1 and that navigation errors made by their axons coincide with regions of high Hs2st and/or Hs6st1 expression at the chiasm. Slit proteins are expressed at particular locations in the retina and around the chiasm and are normally deployed to prevent axons entering inappropriate territories. We show that Hs2st and/or Hs6st1 expression coincides with Slit expression domains at locations where RGC axons make navigation errors in Hs2st(-/-) and Hs6st1(-/-) mutants and that Hs6st1(-/-) RGC axons are less sensitive to Slit2 repulsion than their wild-type counterparts in vitro. We suggest that (1) Hs2st and Hs6st1 are each deployed to generate distinct patterns of heparan sulfation on RGCs and at the optic chiasm and (2) this differential sulfation directs retinal axons through the chiasm, at least in part by modulating the response of the navigating growth cone to Slit proteins.