Jiao Jianwei, Huang Xizhong, Feit-Leithman Rachel Ann, Neve Rachael Lee, Snider William, Dartt Darlene Ann, Chen Dong Feng
Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
EMBO J. 2005 Mar 9;24(5):1068-78. doi: 10.1038/sj.emboj.7600589. Epub 2005 Feb 17.
At a certain point in development, axons in the mammalian CNS undergo a profound loss of intrinsic growth capacity, which leads to poor regeneration after injury. Overexpression of Bcl-2 prevents this loss, but the molecular basis of this effect remains unclear. Here, we report that Bcl-2 supports axonal growth by enhancing intracellular Ca(2+) signaling and activating cAMP response element binding protein (CREB) and extracellular-regulated kinase (Erk), which stimulate the regenerative response and neuritogenesis. Expression of Bcl-2 decreases endoplasmic reticulum (ER) Ca(2+) uptake and storage, and thereby leads to a larger intracellular Ca(2+) response induced by Ca(2+) influx or axotomy in Bcl-2-expressing neurons than in control neurons. Bcl-x(L), an antiapoptotic member of the Bcl-2 family that does not affect ER Ca(2+) uptake, supports neuronal survival but cannot activate CREB and Erk or promote axon regeneration. These results suggest a novel role for ER Ca(2+) in the regulation of neuronal response to injury and define a dedicated signaling event through which Bcl-2 supports CNS regeneration.
在发育的某个阶段，哺乳动物中枢神经系统中的轴突会经历内在生长能力的显著丧失，这导致损伤后再生能力较差。Bcl-2的过表达可防止这种丧失，但这种效应的分子基础仍不清楚。在此，我们报告Bcl-2通过增强细胞内Ca(2+)信号传导并激活环磷酸腺苷反应元件结合蛋白（CREB）和细胞外调节激酶（Erk）来支持轴突生长，这些蛋白刺激再生反应和神经突形成。Bcl-2的表达减少内质网（ER）对Ca(2+)的摄取和储存，从而导致与对照神经元相比，在表达Bcl-2的神经元中，Ca(2+)内流或轴突切断诱导的细胞内Ca(2+)反应更大。Bcl-x(L)是Bcl-2家族的抗凋亡成员，不影响ER对Ca(2+)的摄取，可支持神经元存活，但不能激活CREB和Erk或促进轴突再生。这些结果表明ER Ca(2+)在调节神经元对损伤的反应中具有新作用，并确定了Bcl-2支持中枢神经系统再生的特定信号事件。
