CREB couples neurotrophin signals to survival messages.

There are several interacting pathways for survival, death, bcl-2 transcription, and CREB Ser-133 phosphorylation. Some of this richness is described below. For example, although CREB-dependent activation of bcl-2 transcription is an attractive mechanism to explain neurotrophin-induced survival, the contribution of this pathway to programmed cell death in vivo remains to be established. In vivo, the absence of NGF, its cognate receptor TrkA, or bcl-2 causes overlapping populations of neurons to die. However, significant neurodegeneration in bcl-2−/− mice appears to occur after a time point (P10) when the majority of these neurons are lost in NGF−/− or TrkA−/− mice, and loss of cerebellar granule neurons in bcl-2−/− mice has not been reported (Michaelidis et al. 1996xMichaelidis, T.M, Sendtner, M, Cooper, J.D, Airaksinen, M.S, Holtmann, B, Meyer, M, and Thoenen, H. Neuron. 1996; 17: 75–89Abstract | Full Text | Full Text PDF | PubMed | Scopus (218)See all ReferencesMichaelidis et al. 1996). Moreover, BDNF is capable of promoting the survival of motoneurons following axotomy, even in bcl-2−/− mice (Michaelidis et al. 1996xMichaelidis, T.M, Sendtner, M, Cooper, J.D, Airaksinen, M.S, Holtmann, B, Meyer, M, and Thoenen, H. Neuron. 1996; 17: 75–89Abstract | Full Text | Full Text PDF | PubMed | Scopus (218)See all ReferencesMichaelidis et al. 1996). Thus, additional neurotrophin-dependent signal transduction pathways and CREB target genes may mediate neuronal survival. To test this possibility, it would be interesting to determine if CREB-VP16 can promote the survival of sympathetic neurons or cerebellar granule cells from bcl-2−/− mice.Support for the existence of additional transcription-dependent survival pathways has appeared recently (Figure 2Figure 2). Akt/PKB mediates neuronal survival partly through phosphorylation and inhibition of FKHRL1, a member of the Forkhead family of transcription factors (reviewed by Datta et al. 1999xDatta, S.R, Brunet, A, and Greenberg, M.E. Genes Dev. 1999; 13: 2905–2927Crossref | PubMed | Scopus (3200)See all ReferencesDatta et al. 1999). FKHRL1 phosphorylation prevents it from translocating to the nucleus and upregulating the proapoptotic protein Fas ligand. Recently, the ability of Ca2+ influx to promote granule cell survival was shown to depend partly on the activation of MEF-2-dependent transcription (Mao et al. 1999xMao, Z, Bonni, A, Xia, F, Nadal-Vicens, M, and Greenberg, M.E. Science. 1999; 286: 785–790Crossref | PubMed | Scopus (363)See all ReferencesMao et al. 1999). Taken together, these results establish a commonly held idea—that a major mechanism by which extracellular stimuli such as neurotrophins and neuronal activity regulate the survival of specific populations of developing neurons is through the activation or repression of gene transcription. Thus, a major focus for future research will be to identify the critical target genes that mediate survival and to discover how factors, such as CREB, regulate their transcription.For some survival genes, CREB may need to interact with other promoter-bound factors to achieve physiologic patterns of gene expression. The bcl-2 gene contains an upstream response element (URE) that is adjacent but upstream of the CRE (Wilson et al. 1996xWilson, B.E, Mochon, E, and Boxer, L.M. Mol. Cell Biol. 1996; 16: 5546–5556Crossref | PubMedSee all ReferencesWilson et al. 1996). Although an isolated URE cannot mediate bcl-2 expression, the URE cooperates with the adjacent CRE to attain levels of bcl-2 reporter gene expression that are double those achieved with the CRE alone (Wilson et al. 1996xWilson, B.E, Mochon, E, and Boxer, L.M. Mol. Cell Biol. 1996; 16: 5546–5556Crossref | PubMedSee all ReferencesWilson et al. 1996). In this regard, bcl-2 is organized similar to BDNF, another CREB-regulated gene that mediates neuronal survival. Ca2+-stimulated BDNF transcription depends on interactions within a BDNF promoter between CRE-bound factors and proteins that are bound to an adjacent URE (reviewed by Shieh and Ghosh 1999xShieh, B and Ghosh, A. J. Neurobiol. 1999; 41: 127–134Crossref | PubMed | Scopus (118)See all ReferencesShieh and Ghosh 1999). However, the identity of upstream factors that cooperate with CREB to regulate BDNF or bcl-2 transcription and the significance of the URE/CRE organization remain unknown.Response elements in addition to the URE and CRE may also mediate NGF-induced bcl-2 transcription (Wilson et al. 1996xWilson, B.E, Mochon, E, and Boxer, L.M. Mol. Cell Biol. 1996; 16: 5546–5556Crossref | PubMedSee all ReferencesWilson et al. 1996). Downstream of the known CRE, bcl-2 contains a negative regulatory element that binds the tumor suppressor p53. Kaplan and colleagues recently showed that NGF activation of the Ras/ERK pathway regulates the survival of sympathetic neurons partly by suppressing the p53-mediated cell death pathway (Mazzoni et al. 1999xMazzoni, I.E, Sad, F.A, Aloyz, R, Miller, F.D, and Kaplan, D. J. Neurosci. 1999; 19: 9716–9727PubMedSee all ReferencesMazzoni et al. 1999). Thus, NGF and other neurotrophins might control the expression of bcl-2 positively through CREB and negatively through p53 suppression.The discovery that CREB is a critical regulator of NGF-induced bcl-2 transcription and neuronal survival raises the interesting possibility that CREB and related family members might play a general role in mediating stimulus-dependent cell survival. The critical Ser-133 on CREB that is phosphorylated by RSK-2 is also a target of many other signal transduction pathways besides the Ras/ERK pathway. Several of these pathways, such as protein kinase A (PKA), PKC, and CaMKIV, are activated by extracellular stimuli that promote the survival of some neuronal and nonneuronal cell populations. The observation that mice lacking CREB mostly survive until birth and apparently exhibit limited anatomical and physiological defects could be construed as evidence against a broad role for CREB in survival (Rudolph et al. 1998xRudolph, D, Tafuri, A, Gass, P, Hammerling, G.J, Arnold, B, and Shutz, G. Proc. Natl. Acad. Sci. USA. 1998; 95: 4481–4486Crossref | PubMed | Scopus (233)See all ReferencesRudolph et al. 1998). However, other CREB family members probably substitute for the absence of CREB in these mice (Rudolph et al. 1998xRudolph, D, Tafuri, A, Gass, P, Hammerling, G.J, Arnold, B, and Shutz, G. Proc. Natl. Acad. Sci. USA. 1998; 95: 4481–4486Crossref | PubMed | Scopus (233)See all ReferencesRudolph et al. 1998).CREB has already been implicated in mechanisms of activity-dependent synaptic plasticity (reviewed by Silva et al. 1998xSilva, A.J, Kogan, J.H, Frankland, P.W, and Kida, S. Annu. Rev. Neurosci. 1998; 21: 127–148Crossref | PubMed | Scopus (897)See all ReferencesSilva et al. 1998). Now, the reports from the Ginty and Greenberg laboratories show that CREB also regulates neuronal survival. How does the same transcription factor mediate apparently distinct biological functions? CREB is a single component of a complex of promoter-bound enhancing factors. Whether a particular gene is transcribed in response to a signal is determined by the factors bound to the gene's promoter and the activity of the pathways that regulate the complex. Therefore, specificity may reflect the activity of parallel pathways which regulate factors that cooperate with CREB. However, it is tempting to speculate that the signal transduction pathways and programs of gene expression involved in activity-dependent survival and activity-dependent plasticity may largely overlap. For example, neurotrophic factors, extracellular Ca2+ influx, Ras/ERK pathway activation, and now CREB-dependent transcription have been assigned dual functions, regulating both neuronal survival and synaptic plasticity (reviewed by Curtis and Finkbeiner 1999xCurtis, J and Finkbeiner, S. J. Neurosci. Res. 1999; 58: 88–95Crossref | PubMed | Scopus (99)See all ReferencesCurtis and Finkbeiner 1999). A molecular connection between pathways that regulate survival and plasticity could lend support to the idea that some neurodegenerative disorders may ultimately prove to be a failure of plasticity (Mesulam 1999xMesulam, M.-M. Neuron. 1999; 24: 521–529Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesMesulam 1999).*E-mail: sfinkbeiner@gladstone.ucsf.edu.