初級感覺神經(jīng)元是一種假單極神經(jīng)元，從胞體生長出一根軸突在不遠(yuǎn)處分為外周支和中樞支,。盡管兩分支來自同一根軸突,，但損傷后的再生能力卻截然不同：外周分支損傷后容易再生，而中樞分支損傷后很難再生,。以前的觀點(diǎn)認(rèn)為,，兩分支再生能力的迥異是由其所處環(huán)境的不同所致，但近來越來越多的證據(jù)表明初級感覺神經(jīng)元的內(nèi)在生長因素在該過程中扮演更重要的角色,。目前,，雖然一些促進(jìn)神經(jīng)再生的神經(jīng)元內(nèi)在因素和相應(yīng)分子機(jī)制被揭示，但對神經(jīng)元內(nèi)在的抑制性分子及其作用機(jī)制還知之甚少,。
近日《Journal of Cell Science》發(fā)表了中國科學(xué)院上海生命科學(xué)研究院生物化學(xué)與細(xì)胞生物學(xué)研究所鮑嵐研究組的研究工作：IPP5作為一個神經(jīng)元內(nèi)在因子抑制初級感覺神經(jīng)元突起生長,。IPP5是一個新型的蛋白磷酸酶1（PP1）抑制因子，IPP5從大鼠胚胎14.5天到成年一直選擇性地高表達(dá)在初級感覺神經(jīng)元中,，并且在成年大鼠坐骨神經(jīng)損傷動物模型中顯著下調(diào),。我們的研究發(fā)現(xiàn)，IPP5作為一個神經(jīng)元內(nèi)在因子抑制初級感覺神經(jīng)元突起生長,。這種抑制作用依賴于IPP5與PP1的結(jié)合和對PP1蛋白磷酸酶活性的抑制,，IPP5與PP1、TβRI 受體形成復(fù)合體,，調(diào)控轉(zhuǎn)化生長因子-β（TGF-β）/Smad信號通路來抑制神經(jīng)突起的生長,。該研究揭示了選擇性高表達(dá)在初級感覺神經(jīng)元中的IPP5對其生長的功能調(diào)控和分子細(xì)胞機(jī)制，擴(kuò)展了對神經(jīng)元內(nèi)在的抑制性分子的理解,。該項(xiàng)工作由博士研究生韓清見等在鮑嵐研究員的指導(dǎo)下完成,。
該工作得到了中國科學(xué)院、國家自然科學(xué)基金、科技部蛋白質(zhì)重大研究計劃等項(xiàng)目的資助,。（生物谷Bioon.com）
doi:10.1242/?jcs.114280
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IPP5 inhibits neurite growth in primary sensory neurons by maintaining TGF-β/Smad signaling
Qing-Jian Han1, Nan-Nan Gao1, Guo-QiangMa1, Zhen-Ning Zhang1, Wen-Hui Yu1, Jing Pan1, Qiong Wang1, Xu Zhang2 and Lan Bao1,*
During nerve regeneration, neurite growth is regulated by both intrinsic molecules and extracellular factors. Here, we found that inhibitor 5 of protein phosphatase 1 (IPP5), a newly identified inhibitory subunit of protein phosphatase 1 (PP1), inhibited neurite growth in primary sensory neurons as an intrinsic regulator. IPP5 was highly expressed in the primary sensory neurons of rat dorsal root ganglion (DRG) and was downregulated after sciatic nerve axotomy. Knocking down IPP5 with specific shRNA increased the length of the longest neurite, the total neurite length and the number of neurite ends in cultured rat DRG neurons. Mutation of the PP1-docking motif K8IQF11 or the PP1-inhibiting motif at Thr34 eliminated the IPP5-induced inhibition of neurite growth. Furthermore, biochemical experiments showed that IPP5 interacted with type I transforming growth factor-β receptor (TβRI) and PP1 and enhanced transforming growth factor-β (TGF-β)/Smad signaling in a PP1-dependent manner. Overexpressing IPP5 in DRG neurons aggravated TGF-β-induced inhibition of neurite growth, which was abolished by blocking PP1 or IPP5 binding to PP1. Blockage of TGF-β signaling with the TβRI inhibitor SB431542 or Smad2 shRNA attenuated the IPP5-induced inhibition of neurite growth. Thus, these data indicate that selectively expressed IPP5 inhibits neurite growth by maintaining TGF-β signaling in primary sensory neurons.
