Bcl-2 enhances Ca(2+) 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 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.
Jiao
Jianwei
J
Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
Huang
Xizhong
X
Feit-Leithman
Rachel Ann
RA
Neve
Rachael Lee
RL
Snider
William
W
Dartt
Darlene Ann
DA
Chen
Dong Feng
DF
D000818:Animals; D001369:Axons / Q000502:physiology*; D020013:Calcium Signaling; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008959:Models, Neurological; D016296:Mutagenesis; D009416:Nerve Regeneration / Q000502:physiology*; D016716:PC12 Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000502:physiology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein; D020928:Mitogen-Activated Protein Kinases
EMBO J. 2001 Jun 1;20(11):2690-701
11387204
Dev Neurosci. 1997;19(1):33-41
9078431
Science. 2001 Oct 12;294(5541):333-9
11598293
J Biol Chem. 2001 Nov 23;276(47):44117-28
11546793
Annu Rev Pharmacol Toxicol. 2002;42:135-63
11807168
Neuron. 2002 Apr 25;34(3):371-85
11988169
Cell Mol Neurobiol. 2001 Dec;21(6):591-604
12043835
J Neurosci. 1997 May 15;17(10):3568-79
9133380
Curr Biol. 1997 Oct 1;7(10):798-800
9368763
Invest Ophthalmol Vis Sci. 1997 Nov;38(12):2545-53
9375574
J Neurosci. 1998 Feb 1;18(3):1009-19
9437022
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8339-44
9653188
Neuron. 1998 Jul;21(1):13-26
9697848
J Cell Sci. 2005 Mar 1;118(Pt 5):863-72
15731004
Proc Natl Acad Sci U S A. 2000 May 23;97(11):5723-8
10823933
Annu Rev Neurosci. 2000;23:579-612
10845076
Curr Opin Neurobiol. 2001 Jun;11(3):306-11
11399428
Science. 2002 Jun 7;296(5574):1860-4
12052959
Neuron. 2002 Jun 13;34(6):999-1010
12086646
Neuron. 2002 Aug 15;35(4):605-23
12194863
Apoptosis. 2002 Oct;7(5):441-7
12207177
J Biol Chem. 2002 Nov 1;277(44):41525-32
12191994
Invest Ophthalmol Vis Sci. 2003 Jan;44(1):347-54
12506095
J Cell Biol. 2003 Jan 6;160(1):53-64
12515824
J Biol Chem. 2003 Jan 17;278(3):2021-9
12379660
Cell Calcium. 2002 Nov-Dec;32(5-6):413-20
12543100
Mol Neurobiol. 2003 Feb;27(1):99-106
12668903
J Anat. 2004 Jan;204(1):49-55
14690477
Biochem J. 2004 Oct 15;383(Pt 2):361-70
15245329
Am J Physiol. 1992 Jan;262(1 Pt 1):C171-81
1531101
J Neurobiol. 1993 Apr;24(4):528-43
8515255
Development. 1994 Feb;120(2):301-11
8149910
Neuron. 1994 Oct;13(4):1017-30
7946326
Science. 1995 Apr 14;268(5208):239-47
7716515
Proc Natl Acad Sci U S A. 1995 May 9;92(10):4304-8
7753802
Nature. 1995 Jun 29;375(6534):784-7
7596410
Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7287-91
7638182
Nature. 1997 Jan 30;385(6615):434-9
9009190
Cell Calcium. 2001 Jan;29(1):1-11
11133351