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

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