Heparan Sulfotransferases Hs6st1 and Hs2st Keep Erk in Check for Mouse Corpus Callosum Development
Heparan Sulfotransferases Hs6st1 and Hs2st Keep Erk in Check for Mouse Corpus Callosum Development
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DOI：
10.1523/jneurosci.3157-13.2014
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发表时间：
2014-02-05
影响因子：
5.3
通讯作者：
Pratt, Thomas
中科院分区：
文献类型：
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作者：
Clegg, James M.;Conway, Christopher D.;Pratt, Thomas
在哺乳动物的左右大脑半球之间存在着连接，其发育需要在端脑中线由信号蛋白介导的细胞间通讯。硫酸乙酰肝素(HS)是一种硫化多糖，它修饰细胞表面和细胞外基质蛋白，并通过糖-蛋白相互作用调节多种信号蛋白的生物活性。HS受到受调控的酶法硫化和脱硫的影响，一个吸引人的假说是HS的生物活性受糖硫酸盐密码的调节，尽管这一假说尚未得到证实。缺乏肝素磺基转移酶Hs2st或Hs6st1的突变小鼠胚胎具有严重的CC表型，并形成Probst束不交叉的轴突，两侧是大的中线神经胶质突起。在这里，我们发现在两个突变体中，表达Sox9的神经胶质细胞在灰质束区域早熟积累，在胶质楔形区相应的缺失，与沿吻尾轴形成Probst束有关。在分子上，我们发现在Hs2st(-/-)(2倍)和Hs6st1(-/-)(6倍)胚胎端脑中Erk信号的过度激活在中线最显著，在野生型中Erk信号最低，在Hs6st1(-/-)胚胎中Fgf8蛋白水平增加2倍，这可能支持Erk的过度激活和过度的胶质细胞移动到灰质区。紧密相连的Hs6st1(-/-)CC神经胶质和轴突表型可以通过遗传或药物抑制Fgf8/Erk轴成分来挽救。总体而言，我们的数据符合一个模型，在该模型中，Hs2st和Hs6st1通常通过生成一个包含HS的环境来控制ERK信号，从而产生有利于CC发展的条件。
The corpus callosum (CC) connects the left and right cerebral hemispheres in mammals and its development requires intercellular communication at the telencephalic midline mediated by signaling proteins. Heparan sulfate (HS) is a sulfated polysaccharide that decorates cell surface and extracellular matrix proteins and regulates the biological activity of numerous signaling proteins via sugar-protein interactions. HS is subject to regulated enzymatic sulfation and desulfation and an attractive, although not proven, hypothesis is that the biological activity of HS is regulated by a sugar sulfate code. Mutant mouse embryos lacking the heparan sulfotransferases Hs2st or Hs6st1 have severe CC phenotypes and form Probst bundles of noncrossing axons flanking large tangles of midline glial processes. Here, we identify a precocious accumulation of Sox9-expressing glial cells in the indusium griseum region and a corresponding depletion at the glial wedge associated with the formation of Probst bundles along the rostrocaudal axis in both mutants. Molecularly, we found a surprising hyperactivation of Erk signaling in Hs2st(-/-) (2-fold) and Hs6st1(-/-) (6-fold) embryonic telencephalon that was most striking at the midline, where Erk signaling is lowest in wild-types, and a 2-fold increase in Fgf8 protein levels in Hs6st1(-/-) embryos that could underpin Erk hyperactivation and excessive glial movement to the indusium griseum. The tightly linked Hs6st1(-/-) CC glial and axonal phenotypes can be rescued by genetic or pharmacological suppression of Fgf8/Erk axis components. Overall, our data fit a model in which Hs2st and Hs6st1 normally generate conditions conducive to CC development by generating an HS-containing environment that keeps Erk signaling in check.