FGF8 morphogen gradients are differentially regulated by heparan sulphotransferases Hs2st and Hs6st1 in the developing brain.
FGF8 morphogen gradients are differentially regulated by heparan sulphotransferases Hs2st and Hs6st1 in the developing brain.
复制标题
DOI：
10.1242/bio.028605
复制
发表时间：
2017-12-15
期刊：
影响因子：
2.4
通讯作者：
Pratt T
中科院分区：
文献类型：
--
作者：
Chan WK;Price DJ;Pratt T
成纤维细胞生长因子（FGF）形态发生素通过进化上古老的细胞外信号调节激酶/丝裂原活化蛋白激酶（ERK/MAPK）途径的信号传导在许多神经和非神经发育环境中重现，并且理解调节FGF/ERK功能的机制相应地重要。硫酸乙酰肝素（HS）结合FGF，并存在于大量的差异硫酸化形式产生的HS修饰酶的作用，因此有可能提出一个非常大量的信息在FGF/ERK信号。虽然已经有许多研究表明，HS是一个重要的调节FGF功能，实验证据的作用，不同的HS修饰酶对FGF梯度形成一直缺乏到现在。我们挑战离体发育的小鼠神经组织，其中HS已经通过乙酰肝素酶处理酶促去除或缺乏HS修饰酶Hs 2st（Hs 2st-/-组织）或Hs 6st 1（Hs 6st 1-/-组织），用外源性Fgf 8来深入了解HS和这两种HS修饰酶的功能如何影响外源性Fgf 8蛋白源的Fgf 8梯度形成。我们发现，两种不同的HS修饰酶，Hs 2st和Hs 6st 1，确实差异调节新兴的Fgf 8蛋白浓度梯度和Erk信号输出响应Fgf 8在活组织中的离体培养物的属性。Hs 2st和Hs 6st 1两者都是稳定的Fgf 8梯度所需的，以与它们在野生型组织中一样快速地形成，而与野生型相比，只有Hs 6st 1对抑制梯度中的Fgf 8蛋白水平具有显著作用。接下来，我们表明，Hs 2st和Hs 6st 1的作用，拮抗和激动的Erk信号响应Fgf 8蛋白，分别在活组织的离体培养。Hs 2st −/−和Hs 6st 1 −/−胚胎中内源性Fgf 8蛋白和Erk信号输出的检查表明，我们的离体研究结果具有体内生理相关性。我们的发现确定了一类通过调节Hs 2st和Hs 6st 1的表达来调节Fgf 8功能的新机制，这可能对与HS相互作用的200多种其他信号蛋白及其在神经发育和疾病中的功能具有更广泛的应用。总结：调节细胞表面碳水化合物的精细结构提供了一种微调胚胎小鼠前脑形态梯度形成的机制。
Fibroblast growth factor (FGF) morphogen signalling through the evolutionarily ancient extracellular signalling-regulated kinase/mitogen activated protein kinase (ERK/MAPK) pathway recurs in many neural and non-neural developmental contexts, and understanding the mechanisms that regulate FGF/ERK function are correspondingly important. The glycosaminoglycan heparan sulphate (HS) binds to FGFs and exists in an enormous number of differentially sulphated forms produced by the action of HS modifying enzymes, and so has the potential to present an extremely large amount of information in FGF/ERK signalling. Although there have been many studies demonstrating that HS is an important regulator of FGF function, experimental evidence on the role of the different HS modifying enzymes on FGF gradient formation has been lacking until now. We challenged ex vivo developing mouse neural tissue, in which HS had either been enzymatically removed by heparanase treatment or lacking either the HS modifying enzymes Hs2st (Hs2st−/− tissue) or Hs6st1 (Hs6st1−/− tissue), with exogenous Fgf8 to gain insight on how HS and the function of these two HS modifying enzymes impacts on Fgf8 gradient formation from an exogenously supplied source of Fgf8 protein. We discover that two different HS modifying enzymes, Hs2st and Hs6st1, indeed differentially modulate the properties of emerging Fgf8 protein concentration gradients and the Erk signalling output in response to Fgf8 in living tissue in ex vivo cultures. Both Hs2st and Hs6st1 are required for stable Fgf8 gradients to form as rapidly as they do in wild-type tissue while only Hs6st1 has a significant effect on suppressing the levels of Fgf8 protein in the gradient compared to wild type. Next we show that Hs2st and Hs6st1 act to antagonise and agonise the Erk signalling in response to Fgf8 protein, respectively, in ex vivo cultures of living tissue. Examination of endogenous Fgf8 protein and Erk signalling outputs in Hs2st−/− and Hs6st1−/− embryos suggests that our ex vivo findings have physiological relevance in vivo. Our discovery identifies a new class of mechanism to tune Fgf8 function by regulated expression of Hs2st and Hs6st1 that is likely to have broader application to the >200 other signalling proteins that interact with HS and their function in neural development and disease. Summary: Regulating the fine structure of cell surface carbohydrates provides a mechanism for fine tuning the formation of morphogen gradients in the embryonic mouse fore-brain.
登录
查看更多内容
影响因子：
64.5
作者：
López-Bendito, G;Cautinat, A;Garel, S
通讯作者：
Garel, S
影响因子：
5.3
作者：
Pratt, Thomas;Conway, Christopher D.;Mason, John O.
通讯作者：
Mason, John O.
影响因子：
30.8
作者：
Harada, Masayo;Murakami, Hirotaka;Okawa, Akihiko;Okimoto, Noriaki;Hiraoka, Shuichi;Nakahara, Taka;Akasaka, Ryogo;Shiraishi, Yo-ichi;Futatsugi, Noriyuki;Mizutani-Koseki, Yoko;Kuroiwa, Atsushi;Shirouzu, Mikako;Yokoyama, Shigeyuki;Taiji, Makoto;Iseki, Sachiko;Ornitz, David M.;Koseki, Haruhiko
通讯作者：
Koseki, Haruhiko
影响因子：
4.8
作者：
Ori, Alessandro;Wilkinson, Mark C.;Fernig, David G.
通讯作者：
Fernig, David G.
影响因子：
56.9
作者：
Inatani, M;Irie, F;Yamaguchi, Y
通讯作者：
Yamaguchi, Y