《細(xì)胞》（Cell）雜志于2012年6月22日發(fā)表了上海生科院神經(jīng)所張旭研究組題為“成纖維細(xì)胞生長因子13作為微管穩(wěn)定蛋白調(diào)控神經(jīng)元極性化與遷移”的研究論文,。論文報(bào)道了非分泌型成纖維細(xì)胞生長因子13（Fibroblast growth factor 13,；FGF13）在神經(jīng)元軸突的生長錐中具有聚合和穩(wěn)定微管的功能,，影響軸突和前導(dǎo)突起的生長,；在腦發(fā)育過程中FGF13調(diào)控神經(jīng)元的遷移、大腦皮層和海馬組織結(jié)構(gòu)的形成,，從而影響學(xué)習(xí)與記憶等腦功能,。該項(xiàng)工作由神經(jīng)所博士研究生吳青峰和楊柳等在張旭研究員的指導(dǎo)下完成。
大腦皮層和海馬是形成學(xué)習(xí)與記憶等腦功能的關(guān)鍵腦區(qū),，它們發(fā)育的異常會導(dǎo)致智力障礙。人類X染色體的基因缺陷或變異可以導(dǎo)致大腦發(fā)育遲滯,，造成兒童智力發(fā)育障礙,，稱為X-連鎖智力障礙綜合癥。FGF13基因位于X染色體,，以往的病例研究提示FGF13基因缺陷可能與X-連鎖智力障礙有關(guān),，然而，F(xiàn)GF13在腦發(fā)育中的功能尚不清楚,。
絕大多數(shù)FGF家族成員是分泌性因子,，作用于細(xì)胞膜上受體啟動信號傳導(dǎo)，對細(xì)胞的增殖和分化發(fā)揮著至關(guān)重要的作用，參與胚胎的早期發(fā)育,。FGF13是FGF11亞家族成員,，這類FGF分子因沒有分泌信號肽而無法分泌，在細(xì)胞內(nèi)發(fā)揮功能,。張旭研究組的研究顯示,，在腦發(fā)育過程中FGF13表達(dá)于大腦皮層和海馬神經(jīng)元中，它的剪接異構(gòu)體FGF13B蛋白在神經(jīng)元生長錐中富集,，并且與微管相互作用,。進(jìn)一步的研究表明FGF13B是微管穩(wěn)定蛋白，不僅可以與微管結(jié)合,，具有微管結(jié)合結(jié)構(gòu)域,，而且可以聚合微管蛋白和穩(wěn)定微管，保護(hù)微管免受降解,。他們還發(fā)現(xiàn)FGF13B在大腦皮層中調(diào)節(jié)軸突或前導(dǎo)突起的發(fā)育,，因而調(diào)節(jié)神經(jīng)元遷移，F(xiàn)GF13B缺失會阻礙神經(jīng)元從多極性向雙極性轉(zhuǎn)化,，還導(dǎo)致軸突或前導(dǎo)突起的過度分支,，從而減緩神經(jīng)元的遷移。這些結(jié)果提示FGF13B通過聚合與穩(wěn)定微管來調(diào)控神經(jīng)元發(fā)育,。他們進(jìn)一步發(fā)現(xiàn),，F(xiàn)GF13基因敲除小鼠由于神經(jīng)元遷移遲滯造成大腦皮層和海馬結(jié)構(gòu)分層異常，學(xué)習(xí)記憶能力受到明顯損害,。因此,，缺乏FGF13可以導(dǎo)致大腦皮層和海馬發(fā)育遲滯以及個體智力障礙。該研究闡述了FGF13B對大腦發(fā)育的調(diào)控作用及其機(jī)理,，為智力障礙綜合癥提供了新的分子細(xì)胞機(jī)制,。
該工作得到了中國科學(xué)院、科技部,、國家自然科學(xué)基金委等基金資助,。（生物谷Bioon.com）
doi:10.1016/j.cell.2012.04.046
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Fibroblast Growth Factor 13 Is a Microtubule-Stabilizing Protein Regulating Neuronal Polarization and Migration
Qing-Feng Wu, Liu Yang, Shuai Li, Qiong Wang, Xiao-Bin Yuan, Xiang Gao, Lan Bao, Xu Zhang
Secretory fibroblast growth factors (FGFs) and their receptors are known for their regulatory function in the early stages of neural development. FGF13, a nonsecretory protein of the FGF family, is expressed in cerebral cortical neurons during development and is a candidate gene for syndromal and nonspecific forms of X-chromosome-linked mental retardation (XLMR). However, its function during development remains unclear. We show that FGF13 acts intracellularly as a microtubule-stabilizing protein required for axon and leading process development and neuronal migration in the cerebral cortex. FGF13 is enriched in axonal growth cones and interacts directly with microtubules. Furthermore, FGF13 polymerizes tubulins and stabilizes microtubules. The loss of FGF13 impairs neuronal polarization and increases the branching of axons and leading processes. Genetic deletion of FGF13 in mice results in neuronal migration defects in both the neocortex and the hippocampus. FGF13-deficient mice also exhibit weakened learning and memory, which is correlated to XLMR patients' intellectual disability.
