BBS Faculty Member - Michael Greenberg

Michael Greenberg

Chair, Department of Neurobiology

Harvard Medical School
Goldenson 420
220 Longwood Ave
Boston, MA 02115
Tel: 617-432-2510
Fax: 617-432-3223
Visit my lab page here.

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. For example, we recently employed genome-wide sequencing methods to discover thousands of neuronal activity-regulated distal enhancer elements that function in primary cortical cultures, providing new insights into the mechanism of stimulus-dependent enhancer function. From these and other 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 excitatory synapses, 3) the composition of protein complexes at the pre- and post-synaptic sites, and 4) 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 aims to characterize the role of the MeCP2 protein in activity-dependent neuronal responses. MeCP2 binds to methylated CpG DNA sequences and can act as a transcriptional repressor. MECP2 mutations in humans are responsible for >80% of the cases of Rett Syndrome, a childhood neurodevelopmental disorder that shares some characteristics with autism. We have shown that MeCP2 is acutely phosphorylated in response to neuronal activation. Moreover, disruption of MeCP2 phosphorylation in vivo results in defects in synapse development and behavior. In parallel studies, we have also identified Ube3a as a neuronal activity-regulated gene. Loss-of-function mutations in UBE3A give rise to Angelman syndrome, a severe neurodevelopmental disorder characterized by mental retardation and frequent seizures. We have found that Ube3a regulates excitatory synapse development by controlling the degradation of specific neuronal synaptic proteins. Our ongoing investigation 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.

Last Update: 8/22/2013


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