Activity-Dependent Gene Transcription
Plasticity is a remarkable feature of the brain, allowing neuronal structure
and function to accommodate to patterns of electrical activity. One component of these long-term changes is the activity-driven induction
of new gene expression, which is required for both the long-lasting long-term potentiation of synaptic transmission associated with learning
and memory and the activity-dependent survival events that help to shape and wire the brain during development. Our laboratory has a
long-standing interest in the molecular mechanisms by which neuronal membrane depolarization and subsequent calcium (Ca2+) influx into
the cytoplasm lead to the induction of new gene transcription. By using the induction of the gene that encodes brain-derived neurotrophic
factor (BDNF) as a model, we have found that the ability of Ca2+ influx to induce transcription of this gene is regulated by the route of
Ca2+ entry into the cell, by the pattern of phosphorylation induced on the transcription factor cAMP-response element (CRE)-binding protein
(CREB), and by the complement of active transcription factors recruited to the Bdnf promoter.
Transcription of the Bdnf gene is regulated in a Ca2+- and neuron-selective manner; however, the mechanisms that underlie this selectivity are not known. We have identified several Ca2+-response elements (CaREs) in Bdnf promoter III that confer Ca2+ inducibility. One of these elements represents a binding site for the Ca2+-responsive transcription factor CREB. CREB mediates diverse responses in the nervous system, and it is not known how CREB induces specific patterns of gene expression in response to different extracellular stimuli. We find that Ca2+ influx into neurons induces CREB phosphorylation at Ser133 and two additional sites, Ser142 and Ser143. While CREB Ser133 phosphorylation is induced by many stimuli, phosphorylation at Ser142 and Ser143 is selectively activated by Ca2+ influx. The triple phosphorylation of CREB is required for effective Ca2+ stimulation of CREB-dependent transcription, suggesting that Ca2+ influx triggers a specific program of gene expression in neurons by selectively regulating CREB phosphorylation.
In addition, we have characterized a novel Ca2+-response element, CaRE1, that is required for activity-dependent transcription of Bdnf exon III and have cloned a transcription factor, CaRF, that activates transcription from Bdnf promoter III in a CaRE1-dependent manner. The transcriptional activity of CaRF is regulated in a Ca2+- and neuron-selective manner, suggesting that CaRF may contribute to the activity-dependent induction of Bdnf expression.
Finally, we have also found that the methyl-CpG-binding protein MeCP2 binds selectively to Bdnf promoter III and functions to repress expression of the Bdnf gene. Mutations in MeCP2, a protein that has been proposed to function as a global transcriptional repressor, are the cause of Rett syndrome (RTT), an X-linked progressive neurological disorder. Although the selective inactivation of MeCP2 in neurons is sufficient to confer a Rett-like phenotype in mice, the specific functions of MeCP2 in postmitotic neurons are not known. We have found that membrane depolarization triggers the Ca2+-dependent phosphorylation and release of MeCP2 from Bdnf promoter III, thereby facilitating transcription. These studies indicate that MeCP2 plays a key role in the control of neuronal activity-dependent gene regulation and suggest that the deregulation of this process may underlie the pathology of RTT.
West AE, Chen WG, Dalva MB, Dolmetsch RE, Kornhauser JM, Shaywitz AJ, Takasu MA, Tao X, Greenberg ME. Calcium regulation of neuronal gene expression. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11024-31. Review.
Tao X, West AE, Chen WG, Corfas G, Greenberg ME. A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF. Neuron. 2002 Jan 31;33(3):383-95.
Kornhauser JM, Cowan CW, Shaywitz AJ, Dolmetsch RE, Griffith EC, Hu LS, Haddad C, Xia Z, Greenberg ME CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events. Neuron. 2002 Apr 11;34(2):221-33.
Chen WG, West AE, Tao X, Corfas G, Szentirmay MN, Sawadogo M, Vinson C, Greenberg ME. Upstream stimulatory factors are mediators of Ca2+-responsive transcription in neurons. J Neurosci. 2003 Apr 1;23(7):2572-81
Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 2003 Oct 31;302(5646):885-9.
Other research areas:
Regulation of Translation in Neurons
Neuronal Cell Fate Determination
Neuronal Survival and Apoptosis
Synapse Formation and Maintenance
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