Cosker Katharina E, Shadan Sadaf, van Diepen Michiel, Morgan Clive, Li Michelle, Allen-Baume Victoria, Hobbs Carl, Doherty Patrick, Cockcroft Shamshad, Eickholt Britta J
MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK.
J Cell Sci. 2008 Mar 15;121(Pt 6):796-803. doi: 10.1242/jcs.019166. Epub 2008 Feb 19.
Phosphatidylinositol transfer proteins (PITPs) mediate the transfer of phosphatidylinositol (PtdIns) or phosphatidylcholine (PtdCho) between two membrane compartments, thereby regulating the interface between signalling, phosphoinositide (PI) metabolism and membrane traffic. Here, we show that PITPalpha is enriched in specific areas of the postnatal and adult brain, including the hippocampus and cerebellum. Overexpression of PITPalpha, but not PITPbeta or a PITPalpha mutant deficient in binding PtdIns, enhances laminin-dependent extension of axonal processes in hippocampal neurons, whereas knockdown of PITPalpha protein by siRNA suppresses laminin and BDNF-induced axonal growth. PITPalpha-mediated axonal outgrowth is sensitive to phosphoinositide 3-kinase (PI3K) inhibition and shows dependency on the Akt/GSK-3/CRMP-2 pathway. We conclude that PITPalpha controls the polarized extension of axonal processes through the provision of PtdIns for localized PI3K-dependent signalling.
磷脂酰肌醇转移蛋白（PITPs）介导磷脂酰肌醇（PtdIns）或磷脂酰胆碱（PtdCho）在两个膜区室之间的转移，从而调节信号传导、磷酸肌醇（PI）代谢和膜运输之间的界面。在此，我们表明PITPα在出生后和成年大脑的特定区域富集，包括海马体和小脑。PITPα的过表达，但不是PITPβ或缺乏结合PtdIns能力的PITPα突变体，可增强海马神经元中层粘连蛋白依赖性轴突生长，而通过小干扰RNA（siRNA）敲低PITPα蛋白则抑制层粘连蛋白和脑源性神经营养因子（BDNF）诱导的轴突生长。PITPα介导的轴突生长对磷酸肌醇3激酶（PI3K）抑制敏感，并显示出对Akt/糖原合成酶激酶-3（GSK-3）/ collapsin反应调节蛋白-2（CRMP-2）途径的依赖性。我们得出结论，PITPα通过为局部PI3K依赖性信号传导提供PtdIns来控制轴突生长的极化延伸。
