title: Bcl-2 enhances Ca(2+) signaling to support the intrinsic regenerative capacity of CNS axons.
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 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.
authors.affiliation: Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Jiao
authors.forename: Xizhong
authors.initials: X
authors.lastname: Huang
authors.forename: Rachel Ann
authors.initials: RA
authors.lastname: Feit-Leithman
authors.forename: Rachael Lee
authors.initials: RL
authors.lastname: Neve
authors.forename: William
authors.initials: W
authors.lastname: Snider
authors.forename: Darlene Ann
authors.initials: DA
authors.lastname: Dartt
authors.forename: Dong Feng
authors.initials: DF
authors.lastname: Chen
mesh_terms: 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
chemical_list: 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
references.citation: EMBO J. 2001 Jun 1;20(11):2690-701
references.pmid: 11387204
references.citation: Dev Neurosci. 1997;19(1):33-41
references.pmid: 9078431
references.citation: Science. 2001 Oct 12;294(5541):333-9
references.pmid: 11598293
references.citation: J Biol Chem. 2001 Nov 23;276(47):44117-28
references.pmid: 11546793
references.citation: Annu Rev Pharmacol Toxicol. 2002;42:135-63
references.pmid: 11807168
references.citation: Neuron. 2002 Apr 25;34(3):371-85
references.pmid: 11988169
references.citation: Cell Mol Neurobiol. 2001 Dec;21(6):591-604
references.pmid: 12043835
references.citation: J Neurosci. 1997 May 15;17(10):3568-79
references.pmid: 9133380
references.citation: Curr Biol. 1997 Oct 1;7(10):798-800
references.pmid: 9368763
references.citation: Invest Ophthalmol Vis Sci. 1997 Nov;38(12):2545-53
references.pmid: 9375574
references.citation: J Neurosci. 1998 Feb 1;18(3):1009-19
references.pmid: 9437022
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8339-44
references.pmid: 9653188
references.citation: Neuron. 1998 Jul;21(1):13-26
references.pmid: 9697848
references.citation: J Cell Sci. 2005 Mar 1;118(Pt 5):863-72
references.pmid: 15731004
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5723-8
references.pmid: 10823933
references.citation: Annu Rev Neurosci. 2000;23:579-612
references.pmid: 10845076
references.citation: Curr Opin Neurobiol. 2001 Jun;11(3):306-11
references.pmid: 11399428
references.citation: Science. 2002 Jun 7;296(5574):1860-4
references.pmid: 12052959
references.citation: Neuron. 2002 Jun 13;34(6):999-1010
references.pmid: 12086646
references.citation: Neuron. 2002 Aug 15;35(4):605-23
references.pmid: 12194863
references.citation: Apoptosis. 2002 Oct;7(5):441-7
references.pmid: 12207177
references.citation: J Biol Chem. 2002 Nov 1;277(44):41525-32
references.pmid: 12191994
references.citation: Invest Ophthalmol Vis Sci. 2003 Jan;44(1):347-54
references.pmid: 12506095
references.citation: J Cell Biol. 2003 Jan 6;160(1):53-64
references.pmid: 12515824
references.citation: J Biol Chem. 2003 Jan 17;278(3):2021-9
references.pmid: 12379660
references.citation: Cell Calcium. 2002 Nov-Dec;32(5-6):413-20
references.pmid: 12543100
references.citation: Mol Neurobiol. 2003 Feb;27(1):99-106
references.pmid: 12668903
references.citation: J Anat. 2004 Jan;204(1):49-55
references.pmid: 14690477
references.citation: Biochem J. 2004 Oct 15;383(Pt 2):361-70
references.pmid: 15245329
references.citation: Am J Physiol. 1992 Jan;262(1 Pt 1):C171-81
references.pmid: 1531101
references.citation: J Neurobiol. 1993 Apr;24(4):528-43
references.pmid: 8515255
references.citation: Development. 1994 Feb;120(2):301-11
references.pmid: 8149910
references.citation: Neuron. 1994 Oct;13(4):1017-30
references.pmid: 7946326
references.citation: Science. 1995 Apr 14;268(5208):239-47
references.pmid: 7716515
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4304-8
references.pmid: 7753802
references.citation: Nature. 1995 Jun 29;375(6534):784-7
references.pmid: 7596410
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7287-91
references.pmid: 7638182
references.citation: Nature. 1997 Jan 30;385(6615):434-9
references.pmid: 9009190
references.citation: Cell Calcium. 2001 Jan;29(1):1-11
references.pmid: 11133351