Activity-dependent changes in gene expression underlie cognitive processes such as learning and memory. Mutations in components of the signaling network that controls the activity-dependent gene program can lead to a variety of neurological disorders including Rett Syndrome, Coffin Lowry Syndrome, and Rubinstein-Tabi Syndrome. Building on two decades of research into the mechanisms by which neuronal activity regulates gene transcription during nervous system development we have recently found that MEF2 family transcription factors act to restrict the number of excitatory synapses that form onto neurons. In this application we describe a series of experiments that will characterize the mechanisms by which MEF2 regulates synapse development and function. We propose the following specific aims: 1) To characterize new components of the signaling network that regulates MEF2 activity during the development and refinement of synaptic connections. We will seek to characterize the nature of neuronal MEF2 transcriptional complexes to gain a thorough understanding of the mechanisms by which neuronal activity regulates MEF2 function. 2) To investigate the importance of MEF2 as a regulator of synapse number in vivo by disrupting MEF2 function in organotypic cultures and in mice. 3) To employ genome-wide strategies to identify and characterize the MEF2 targets that control synapse number. It is our hope that the proposed experiments will provide a better understanding of the role of MEF2 in synapse development and may ultimately provide new insights into the importance of this activity-regulated gene program for both human cognition and disease. Relevance: New gene expression induced by neuronal activity is thought to mediate long-term changes in neuronal function, and mutations in components of this gene expression program cause profound defects in human cognitive function. This proposal seeks to investigate how a family of regulatory factors that controls gene expression leads to alterations in neuronal connectivity, as well as the potential relevance of this process to human cognition and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028829-23
Application #
8033259
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
1990-08-01
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2013-02-28
Support Year
23
Fiscal Year
2011
Total Cost
$517,956
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Mardinly, A R; Spiegel, I; Patrizi, A et al. (2016) Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons. Nature 531:371-5
Andzelm, Milena M; Cherry, Timothy J; Harmin, David A et al. (2015) MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers. Neuron 86:247-63
Bloodgood, Brenda L; Sharma, Nikhil; Browne, Heidi Adlman et al. (2013) The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature 503:121-5
Chahrour, Maria H; Yu, Timothy W; Lim, Elaine T et al. (2012) Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet 8:e1002635
Hemberg, Martin; Gray, Jesse M; Cloonan, Nicole et al. (2012) Integrated genome analysis suggests that most conserved non-coding sequences are regulatory factor binding sites. Nucleic Acids Res 40:7858-69
Ross, Sarah E; McCord, Alejandra E; Jung, Cynthia et al. (2012) Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit assembly. Neuron 73:292-303
Ross, Sarah E; Mardinly, Alan R; McCord, Alejandra E et al. (2010) Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65:886-98
Kim, Tae-Kyung; Hemberg, Martin; Gray, Jesse M et al. (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465:182-7
Greer, Paul L; Hanayama, Rikinari; Bloodgood, Brenda L et al. (2010) The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140:704-16
Fiore, Roberto; Khudayberdiev, Sharof; Christensen, Mette et al. (2009) Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels. EMBO J 28:697-710

Showing the most recent 10 out of 40 publications