Michael Greenberg, Ph.D.
Chairperson, Department of Neurobiology
Our interactions with the outside world trigger changes at neuronal synapses that are critical for proper brain development and higher cognitive function. Research in the Greenberg laboratory has focused on the identification of a genetic program that is activated by neuronal activity, the mechanisms of signal transduction that carry the neuronal activity-dependent signal from the membrane to the nucleus, and the identification of regulators of this experience-dependent process that affect synapse development and plasticity. We are particularly interested in those activity-dependent processes whose dysfunction can lead to the development of diseases of cognitive function.
This work began in 1984 with the discovery that growth factors induce the rapid and transient expression of a family of genes, Immediate Early Genes (IEGs) such as c-fos, whose functions are crucial for neuronal differentiation, cell survival, and adaptive responses (Greenberg and Ziff, 1984). Our recent studies have used more global screening techniques to identify genes whose activity is regulated by stimuli such as membrane depolarization and calcium influx. From these studies we have identified a number of activity-dependent genes that control various processes such as 1) the complexity of the dendritic arbor, 2) the formation, maturation, and maintenance of spines, the post-synaptic sites of most excitatory synapses, 3) the composition of protein complexes at the pre- and post-synaptic sites, 4) the local regulation of protein translation at the synapse by micro-RNAs, and 5) the relative number of excitatory and inhibitory synapses. Many disorders of human cognition, including various forms of mental retardation and autism, are correlated with changes in the number of synapses or are believed to be caused by an imbalance between neuronal excitation and inhibition in the nervous system. Thus, understanding how the neuronal activity-dependent gene program functions may provide insight into the molecular mechanisms that govern synaptic development and, ultimately, how the deregulation of this process leads to neurological diseases.
One of our current projects is to characterize the mechanisms that control the activity-induced transcription of the gene that encodes Brain-Derived Neurotrophic Factor (BDNF). Given the importance of BDNF for proper development of the central nervous system and neuronal plasticity, we have investigated the signaling mechanisms that mediate Ca2+-dependent BDNF transcription. These studies have revealed that the control of BDNF expression in the brain is complex – there are five transcriptional promoters of BDNF in mammals that generate a host of mRNA transcripts which all give rise to an identical BDNF protein. Promoter IV is the most highly induced by Ca2+ influx in vivo and is expressed in the mammalian brain. There are several positive regulators of BDNF promoter IV expression, including CREB, USFs, and CaRF, and one negative regulator, MeCP2. MeCP2 binds to methylated CpG’s in the mammalian promoter IV region of BDNF and acts as a transcriptional repressor in the absence of neuronal activity. However, in response to neuronal activity, MeCP2 is phosphorylated and BDNF expression is de-repressed, leading to effects on dendritic arborization and spine morphology. Interestingly, mutations in MeCP2 in humans are responsible for 80% of the cases of Rett Syndrome, a childhood neurodevelopmental disorder that shares some characteristics with autism. Our data suggests a general model in which experience-dependent stimuli trigger the dynamic modification of proteins such as MeCP2, leading to their altered function in key processes such as nervous system development and synaptic plasticity. Our studies of the many molecular players in the activity-regulated gene program should provide new insights into the mechanisms by which neuronal activity shapes the development of the central nervous system.
For a complete listing of Mike Greenberg's publications on PubMed, click here.