Activity-Dependent Gene Transcription

Synaptic plasticity is mediated in part through the activity-dependent induction of new gene transcription and translation. Transcription of the Bdnf gene is rapidly induced in response to neuronal activity. In quiescent neurons, Bdnf transcription is kept off by by MeCP2, a methyl-DNA binding protein and transcriptional repressor that is mutated in Rett's Syndrome, an inherited form of mental retardation. In response to membrane depolarization, MeCP2 is rapidly phosphorylated and released from the Bdnf promoter. Simultaneously, calcium signaling pathways activate at least three transcription factors that drive Bdnf expression. These factors include the canonical activity-regulated transcription factor CREB, the bHLH family proteins USF1/2, and the novel transcription factor CaRF, which regulates transcription in a calcium- and neural-selective manner. Identification of activity-inducible phosphorylation sites on these factors will facilitate amore detailed understanding of the functional regulation of this transcriptional complex. Once synthesized, BDNF regulates neuronal function in part through the local control of protein translation. A genome-wide screen identified mRNAs whose translation is regulated in neurons by BDNF via the mTOR signaling pathway in immature (4 DIV) or mature (14 DIV) neurons. Many of the BDNF-regulated mRNAs in mature neurons encode proteins that function at synapses, supporting the hypothesis that BDNF-induced translation of specific mRNAs is relevant for synaptic function. At least one of these mRNAs, Homer 2, is localized in dendrites and locally translated at synapses in response to BDNF stimulation. The further characterization of these BDNF-regulated mRNAs should enhance our understanding of how BDNF regulates axonal and dendritic function.

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.

Research Areas: Ca++ Signaling Pathways | Synapse Formation
Neuronal Survival and Apoptosis | Neuronal Development | Neuronal Adaptive Responses

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