Chadborn Neil H, Ahmed Aminul I, Holt Mark R, Prinjha Rabinder, Dunn Graham A, Jones Gareth E, Eickholt Britta J
MRC Centre for Developmental Neurobiology, King's College London, Guy's Campus, London, SE1 1UL, UK.
J Cell Sci. 2006 Mar 1;119(Pt 5):951-7. doi: 10.1242/jcs.02801.
Distinct changes in glycogen synthase kinase-3 (GSK-3) signalling can regulate neuronal morphogenesis including the determination and maintenance of axonal identity, and are required for neurotrophin-mediated axon elongation. In addition, we have previously shown a dependency on GSK-3 activation in the semaphorin 3A (Sema3A)-mediated growth-cone-collapse response of sensory neurons. Regulation of GSK-3 activity involves the intermediate signalling lipid phosphatidylinositol 3,4,5-trisphosphate, which can be modulated by phosphatidylinositol 3-kinase (PI3K) and the tumour suppressor PTEN. We report here the involvement of PTEN in the Sema3A-mediated growth cone collapse. Sema3A suppresses PI3K signalling concomitant with the activation of GSK-3, which depends on the phosphatase activity of PTEN. PTEN is highly enriched in the axonal compartment and the central domain of sensory growth cones during axonal extension, where it colocalises with microtubules. Following exposure to Sema3A, PTEN accumulates rapidly at the growth cone membrane suggesting a mechanism by which PTEN couples Sema3A signalling to growth cone collapse. These findings demonstrate a dependency on PTEN to regulate GSK-3 signalling in response to Sema3A and highlight the importance of subcellular distributions of PTEN to control growth cone behaviour.
糖原合成酶激酶-3（GSK-3）信号通路的明显变化可调节神经元形态发生，包括轴突身份的确定和维持，并且是神经营养因子介导的轴突伸长所必需的。此外，我们之前已经表明，感觉神经元在信号素3A（Sema3A）介导的生长锥塌陷反应中依赖于GSK-3的激活。GSK-3活性的调节涉及中间信号脂质磷脂酰肌醇3,4,5-三磷酸，其可被磷脂酰肌醇3-激酶（PI3K）和肿瘤抑制因子PTEN调节。我们在此报告PTEN参与Sema3A介导的生长锥塌陷。Sema3A抑制PI3K信号传导，同时激活GSK-3，这依赖于PTEN的磷酸酶活性。在轴突延伸过程中，PTEN在轴突区室和感觉生长锥的中央结构域中高度富集，在那里它与微管共定位。暴露于Sema3A后，PTEN迅速在生长锥膜上积累，这表明PTEN将Sema3A信号传导与生长锥塌陷联系起来的一种机制。这些发现证明了依赖PTEN来调节对Sema3A作出反应的GSK-3信号传导，并突出了PTEN的亚细胞分布对控制生长锥行为的重要性。
