CREB family transcription factors inhibit neuronal suicide
Ted M. Dawson1, 2
& David D. Ginty2, 3
1 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
tdawson@jhmi.edu
2 Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
3 Department of Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA dginty@hjmi.edu
Neurodenerative disorders such as Huntington disease lead to neuronal cell death in discrete regions of brain. A new study implicates the CREB transcription factor family as critical mediators that prevent such neuronal death.
Cell death in the nervous system has been a subject of intense investigation in the last several years. The field is driven by the knowledge that the identification of factors that promote neuronal survival may provide therapeutic opportunities for the treatment of a variety of neurodegenerative disorders. In the May issue of Nature Genetics, Schutz and colleagues1 may present such an opportunity: they elegantly demonstrate that the transcription factors cAMP-element binding protein (CREB) and cAMP response modulatory protein (CREM) promote survival of neurons during development and adulthood. Strikingly, mice lacking both CREB and CREM show progressive neurodegeneration. This phenotype closely parallels the neurodegeneration that occurs in Huntington disease (HD), a chronic neurodegenerative disease that strikes in middle age. The new findings are consistent with observations of transcriptional dysregulation in HD and related polyglutamine repeat disorders and suggest that disruption of CREB family−mediated survival pathways has a critical role in the pathogenesis of these disorders. (Fig. 1)
Figure 1. Under normal conditions, CREB family transcription factors promote expression of genes that contribute to neuronal survival.
Deletion of Creb and Crem in neurons of the developing CNS results in apoptosis, and postnatal ablation of these genes results in neuronal degeneration in adulthood. Neurons of the adult striatum and hippocampus are particularly vulnerable to CREB/CREM deficiency. Other recent work has indicated that polyglutamine-dependent sequestration of key effectors of CREB, such as CBP and P/CAF, also leads to apoptosis and may underlie neurodegeneration of striatal neurons in Huntington disease. The striking similarities between mice lacking CREB and CREM and models of HD suggest that a deficiency in CREB-dependent transcription contributes to degeneration of striatal neurons in HD.
The CREB transcription factor family consists of CREB, CREM and activating transcription factor 1 (ATF1)2. These leucine zipper−containing transcription factors regulate expression of a wide variety of genes that contain cAMP-response elements (CREs) within their promoters. CREB regulates the expression of genes through the coordinated action of transcriptional coactivators, such as the CREB-binding protein (CBP). CREB-family transcription factors are activated by phosphorylation and have critical roles in the response to many signal transduction cascades activated by hormones, growth factors, bursts of synaptic activity and other cellular stimuli. Intracellular signaling pathways that promote CREB-dependent transcription include the Ras/MAPK, Ca2+/CaMK, PI3K/Akt and cAMP/PKA pathways. In the nervous system, CREB likely has a critical role in neuronal plasticity and long-term memory. Recent in vitro studies suggest that it also acts to protect neurons against cell death. For example, interfering with normal CREB activity by expressing dominant-negative CREB mutants leads to diminished survival of cultured sympathetic and cerebellar granule neurons. Furthermore, a constitutively active CREB variant can support neuronal survival in the absence of factors normally required to keep nerve cells alive3,
4.
Until now, the function of CREB in the adult nervous system has been difficult to determine, because CREB-null mice die around the time of birth. Also, CREM upregulation may compensate for the lack of CREB in some organs, including the brain. Mutant analysis is probably not hindered by upregulation of the third family member, ATF1, as it is not expressed highly in neurons. To address CREB/CREM-mediated signaling in the nervous system, Schutz and colleagues generated mice with a conditional mutation of the Creb gene1. They used a Cre-loxP gene targeting strategy that allowed them to excise the Creb gene in specific tissues. They examined mice lacking CREB in all neuronal and glial progenitors, or in postnatal forebrain or postnatal striatum. Despite extensive loss of CREB in brains of the various Creb conditional mutants, no other significant abnormalities were identified in these mice other than strong compensatory upregulation of CREM. The author's next step, then, was to breed Creb conditional mice with Crem-/- mice to selectively remove both CREB and CREM. The authors found that dual inactivation of both Creb and Crem in neuronal and glial precursors led to generalized neuronal cell death, particularly in newborn animals. These animals also suffered from premature death. Dramatically, when both Creb and Crem were disrupted in the brain after birth, progressive mid-life neurodegeneration resulted. The degeneration was confined to the dorsolateral striatum and CA1 and dentate gyrus fields of the hippocampus.
These results providing compelling evidence that CREB-family transcription factors have a fundamental role in the survival of neurons in vivo. Mice lacking CREB also exhibit excess death of neurons in the developing peripheral nervous system5. Thus, it is now clear that CREB family members act as general survival factors by controlling the transcription of anti-death or cell survival−promoting genes. But how do they do it? The authors ruled out one obvious possibility—that CREB acts through modulating levels of expression of pro-survival and pro-apoptotic members of the Bcl-2 family. Bcl-2 itself is implicated as a CREB target, but the authors found no alterations in expression of Bcl-2 family members in brain neurons lacking both CREB and CREM. In the future, identification of CNS neuron survival factors whose expression is dependent on CREB will provide fresh insights into neuronal survival and maintenance, and potentially could identify novel therapeutic targets for neurodegenerative disorders.
A particularly important feature of the new findings is the preferential degeneration of the striatum in mice lacking both CREB and CREM. This presents fascinating parallels with HD, which also leads to the preferential loss of neurons in the striatum. HD is due to the expansion of polyglutamine repeats in the huntingtin gene. Several lines of evidence suggest that expanded polyglutamine repeats within huntingtin interact with and sequester transcriptional cofactors. Remarkably, polyglutamine repeat proteins interact with key effectors of CREB, CBP and P/CAF, as well as the coactivator TAFII130, displacing them from their normal nuclear locations6,
7,
8,
9,
10. The polyglutamine expansion of huntingtin may thus interfere with both CBP and CREB-mediated transcription9,
10, resulting in death of cultured neurons9.
The CREB effectors CBP and P/CAF have intrinsic acetyltransferase (HAT) activity, which appears to be impaired in polyglutamine disorders. Consistent with the latter notion are observations that enhancing levels of acetylation with deacetylase inhibitors prevents apoptosis of cultured cells caused by nuclear-targeted polyglutamine11 and rescues transgenic flies from the degenerative effects of mutant huntingtin8.
CBP and other HATs associate with a large number of transcription factors, so the mechanism by which their sequestration by polyglutamine expansion proteins results in apoptosis is still unclear. Neuronal degeneration may be due to compromised levels of CREB-dependent transcription or diminished activities of other transcription factors. The extraordinary degeneration of striatal neurons in CREB/CREM mutant mice lends support to a model in which a deficiency in CREB signaling accounts for neuronal loss associated with HD.
The new findings may also help explain a paradox of HD—projection neurons of the striatum are selectively lost in patients with HD despite the fact that huntingtin is widely expressed in both neuronal and non-neuronal cells. The observation that non-striatal regions of the brain, including the nucleus accumbens, remain largely unaffected by the loss of CREB and CREM may provide a clue. Indeed, many of the same neurons unaffected by CREB/CREM loss are also spared in patients with HD. Perhaps adult striatal neurons are unusually dependent on CREB-dependent transcription for survival, rendering them particularly vulnerable to polyglutamine-mediated depletion of CREB effectors. Lastly, Schutz and colleagues also provide strong evidence for the idea that excess apoptosis can account for the slow neurodegeneration that occurs in patients with devastating neurodegenerative disorders such as HD. The work of Schutz and colleagues should give direction to future research examining the relationship between transcription and apoptosis in neurodegenerative disorders.
Mantamadiotis, T. et al. Disruption of CREB function in brain leads to neurodegeneration. Nature Genet.31, 47–54 (2002). | Article | PubMed | ISI | ChemPort |
Mayr, B. & Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nature Rev. Mol. Cell. Biol.2, 599–609 (2001). | Article | PubMed | ISI | ChemPort |
Bonni, A. et al. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science286, 1358–1362 (1999). | Article | PubMed | ISI | ChemPort |
Riccio, A., Ahn, S., Davenport, C.M., Blendy, J.A. & Ginty, D.D. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science286, 2358–2361 (1999). | Article | PubMed | ISI | ChemPort |
Lonze, B.E., Riccio, A., Cohen, S. & Ginty, D.D. Apoptosis, axonal growth defects and degeneration of peripheral neurons in mice lacking CREB. Neuron (in the press).
McCampbell, A. et al. CREB-binding protein sequestration by expanded polyglutamine. Hum. Mol. Genet.9, 2197–2202 (2000). | Article | PubMed | ISI | ChemPort |
Steffan, J.S. et al. The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl. Acad. Sci. USA97, 6763–6768 (2000). | Article | PubMed | ChemPort |
Nucifora, F.C., et al. Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science291, 2423–2428 (2001). | Article | PubMed | ISI | ChemPort |
Shimohata, T. et al. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nature Genet.26, 29–36 (2000). | Article | PubMed | ISI | ChemPort |
McCampbell, A. et al. Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc. Natl. Acad. Sci. USA98, 15179–15184 (2001). | Article | PubMed | ChemPort |
