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24 (5): 1068-1078

Copyright © 2005 by the European Molecular Biology Organization.

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

Jianwei Jiao1,4,5, Xizhong Huang1, Rachel Ann Feit-Leithman1, Rachael Lee Neve2, William Snider3, Darlene Ann Dartt1, and Dong Feng Chen1,4,5,+

1 Schepens Eye Research Institute, Harvard Medical School, Boston, MA, USA
2 Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA
3 University of North Carolina, Neuroscience Center, Chapel Hill, NC, USA
4 Program in Neuroscience, Harvard Medical School, Boston, MA, USA
5 Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

Abstract: 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-xL, 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.

Key Words: axon growth potential • Bcl-2 • calcium • CREB • Erk

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