The accumulation of a GFP-labeled subunit (GFP-p65) of NF-kB in the nucleus of a neuron following stimulation. Fluorescence recovery after photobleaching (FRAP) was used to reveal the nuclear translocation of the NF-kB transcription factor from distal processes.

Our research goal is to understand the role of the regulation of gene expression in the success or failure of the central nervous system (CNS) to adapt to change. Neuronal plasticity is a fundamental process believed to underlie the remarkable ability of our brain to respond to varied inputs and novel challenges. Plasticity encompasses the modifications in neuronal architecture, connectivity, and function that are inherent to learning and memory, as well as development and response to injury.

General principles of adaptive regulation which interest the lab include: the modulation of gene expression by synaptic signaling, mechanisms for transducing signals between the synapse and the nucleus, pathways for generating input-specific changes in gene expression, the interaction and regulation of transcription factors to generate distinct and overlapping functions, and the influence of plastic changes in gene expression on enduring alterations of neuronal function and animal behavior. The function of the Nuclear Factor kappa B (NF-kB) transcription factor in neurons of the CNS, as well as mechanisms for localized translational regulation are being used as model systems to approach these questions.

NF-kB is held latent in the cytoplasm of most cells by the inhibitory IŁeB proteins. Activating stimuli release NF-kB which moves to the nucleus where it modulates gene transcription after binding to its cognate DNA motifs. The function of the NF-kB family of transcription factors has become a classical paradigm in modern cell biology. Not only do we know most members of this family, we have also gained an understanding of their three dimensional structures, their physiological functions, and signaling pathways leading to NF-kB activation. The groundwork and available tools have now primed this field for investigation in the CNS.

The study of NF-kB provides a good vantage point from which to explore transcriptional regulation in neurons. NF-kB has recently emerged as a key player in many CNS diseases, including neurodegenerative disorders and cancer. Functions for NF-kB in the healthy CNS have also been discovered, including an evolutionarily conserved requirement for NF-kB in learning and memory. We have demonstrated that NF-kB is present at synapses and can undergo activation and nuclear translocation from distal processes upon synaptic stimulation. In addition, our behavioral studies revealed a role for NF-kB in mammalian spatial learning. A current focus of our lab is to understand the signaling mechanisms of synaptic NF-kB and how NF-kB regulates neuronal functions in both plasticity and disease.

Publications:

Cynthia K. Shrum, Daniel Defrancisco, and Mollie K. Meffert. (2009) Stimulated Nuclear Translocation of NF-kB and Shuttling Differentially Depend on Dynein and the Dynactin Complex. PNAS, 106; 2647-2652. PMID: 19196984

Matthew C. Boersma and Mollie K. Meffert (2008) Novel roles for the NF-kB signaling pathway in regulating neuronal function. Science Signaling 1, pe7. PMID: 18272467

Cynthia K. Shrum and Mollie K. Meffert (2008). The NF-kB Family in Learning and Memory. In J. David Sweatt(Ed.), Molecular Mechanisms of Memory. Vol. [4] of Learning and Memory: A Comprehensive Reference (J.Byrne Editor), pp. [567-586] Oxford: Elsevier

Mark P. Mattson and Mollie K. Meffert (2006). Roles for NF-ęB in nerve cell survival, plasticity, and disease. Cell Death and Differentiation 13, 852-60. PMID: 16397579

Mollie K. Meffert and David Baltimore (2005). Physiological functions for brain NF-ęB. Trends in Neurosciences 28, 37-43. PMID: 15626495

Mollie K. Meffert, Jolene M. Chang, Brian J. Wiltgen, Michael S. Fanselow, David Baltimore (2003). NF-ęB functions in synaptic signaling and behavior. Nature Neuroscience 6, 1072 - 1078. PMID: 12947408

Mollie K. Meffert, Nicole C. Calakos, Richard H. Scheller, Howard Schulman (1996). Nitric oxide modulates synaptic vesicle docking / fusion reactions. Neuron 16, 1229-1236. PMID: 8663999

Mollie K. Meffert, Brett A. Premack, and Howard Schulman (1994). Nitric oxide stimulates calcium-independent synaptic vesicle release. Neuron 12, 1235-1244. PMID: 7912090

Mollie K. Meffert, Jane E. Haley, Erin M. Schuman, Howard Schulman, and Daniel V. Madison (1994). Inhibition of hippocampal heme oxygenase, nitric oxide synthase and long-term potentiation by metalloporphyrins. Neuron 13, 1225-1233. PMID: 7524564