Bcl-2 enhances Ca2+ signaling to support the intrinsic regenerative capacity of CNS axons

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 Ca2+ 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) Ca2+ uptake and storage, and thereby leads to a larger intracellular Ca2+ response induced by Ca2+ 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 Ca2+ uptake, supports neuronal survival but cannot activate CREB and Erk or promote axon regeneration. These results suggest a novel role for ER Ca2+ in the regulation of neuronal response to injury and define a dedicated signaling event through which Bcl-2 supports CNS regeneration.