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Mollie K. Meffert
Mollie K. Meffert
725 N. Wolfe Street
413 Physiology Building
Baltimore MD 21205
The Regulation of Neuronal Gene Expression in Health and Disease
Our laboratory is particularly interested in how changes in synaptic activity are converted into long-term alterations in the function and connectivity of neurons through the modulation of gene expression. Fundamental questions in gene expression of interest to the lab include: Why are changes in gene expression required for enduring alterations in synaptic strength, such as during learning, development, or disease? What pathways exist to generate distinct subcellular changes in gene expression, for example to regulate individual synapse protein composition and input specificity? How do diverse neuronal stimuli induce specific patterns of gene expression on a synapse, cellular, or network level? What mechanisms maintain changes in gene expression? Our laboratory integrates multiple approaches to address the importance of gene expression in information storage at both transcriptional and post-transcriptional levels. We use animal models and techniques of molecular biology, cell biology, biochemistry, high-throughput expression analysis and bioinformatics, virology, histology, confocal imaging, electrophysiology, mouse genetics and behavior. Neuronal gene products of interest include both proteins and non-coding RNAs.
Study of the NF-kB transcription factor provides a good vantage point from which to explore transcriptional regulation in neurons. NF-kB has emerged as a key player in many CNS diseases, including neurodegenerative disorders and cancer. In the healthy CNS, studies from multiple laboratories including our own have demonstrated an evolutionarily conserved requirement for NF-kB in learning and memory. NF-kB is present at synapses and can undergo activation and nuclear translocation from distal processes upon synaptic stimulation. A current focus of our lab is to understand the signaling by the synaptic pool of NF-kB and how NF-kB regulates neuronal functions in both plasticity and disease. Gene expression in the nervous system can be rapidly altered by control at the level of translation. Changes in translation, like transcription, are also critical for long-term information storage.
A second major focus of our laboratory investigates how target specificity is generated in response to neuronal stimuli that regulate protein synthesis. We have discovered that the translating pool of RNA may be controlled through both positive and negative regulation of the biogenesis of mature microRNA from precursor microRNA. Ongoing investigations in our laboratory are aimed at further exploration of the importance of micoRNA biogenesis in determining rapid and specific changes in the neuronal and synaptic proteome and the in vivo roles of these pathways in healthy and dysregulated brain function. Videos showing increased mRNA repression (RNA-processing bodies) in live neurons responding to BDNF: Messenger RNA accumulates in a neuron BDNF-treated neuron
Amen, A.M., Ruiz, C.R., Shi J., Subramanian, M., Pham, D.L., and Meffert,M.K. (2017) A rapid induction mechanism for Lin28a in trophic responses. Molecular Cell, 65 (3); 490 - 503.
Subramanian, M., Timmerman, C.K., Schwartz,J.L., Pham,D.L., and Meffert, M.K. (2015), Characterizing Autism Spectrum Disorders by Key Biochemical Pathways. Frontiers in Neuroscience, 9: 313.
Amen,A.M., Pham D.L., and Meffert M.K. (2016) Posttranscriptional regulation by Brain-Derived Neurotrophic Factor in the nervous system. In KMJ Menon and A.Aron Goldstrohm (Ed) Post-transcriptional regulation of endocrine function. Springer Press, p315-337.
Mihalas A.B. and Meffert, M.K. (2015) IKK Kinase Assay for Assessment of Canonical NF-kB Activation in Neurons. Methods in Molecular Biology. v.1280, 61-74.
Ruiz, C.R., Shi, J.,and Meffert, M.K. (2014). Transcript Specificity in BDNF-regulated Protein Synthesis. Neuropharmacol. (Special Issue: BDNF regulation of synaptic structure, function, and plasticity),76; 657-63.
Mihalas, A.B., Araki Y., Huganir, R.L., and Meffert, M.K.(2013), Opposing action of NF-kB and Polo-like kinases determines a homeostatic endpoint for excitatory synaptic adaptation. J.Neurosci.,16; 16490-501.
Huang, Y.A.*, Ruiz, C.R.*, Eyler C.H.*, Lin K., and Meffert, M.K. (2012), Dual regulation of miRNA biogenesis generates target specificity in neurotrophin-induced protein synthesis. Cell, 148(5); 933-946.
Boersma, M.C.*, Dresselhaus, E.C.*, De Biase, L.M., Mihalas, A.B., Bergles, D.E., and Meffert, M.K. (2011), A requirement for NF-kB in developmental and plasticity-associated synaptogenesis. J.Neurosci., 31; 5414-5425.
Shrum, C.K., Defrancisco, D., and Meffert, M.K. (2009) Stimulated nuclear translocation of NF-kB and shuttling differentially depend on dynein and the dynactin complex. PNAS, 106; 2647-2652.
Boersma, M.C., and Meffert, M.K. (2008) Novel roles for the NF-kB signaling pathway in regulating neuronal function. Science Signaling 1, pe7.
Mattson, M.P. and Meffert, M.K. (2006). Roles for NF-kB in nerve cell survival, plasticity, and disease. Cell Death and Differentiation 13, 852-60.
Meffert, M.K. and Baltimore, D. (2005). Physiological functions for brain NF-kB. Trends in Neurosciences 28, 37-43.
Meffert, M.K., Chang, J.M., Wiltgen, B.J., Fanselow, M.S., Baltimore, D. (2003). NF-kB functions in synaptic signaling and behavior. Nature Neuroscience 6, 1072 - 1078.
Meffert, M.K., Calakos, N.C., Scheller, R.H., Schulman H. (1996). Nitric oxide modulates synaptic vesicle docking / fusion reactions. Neuron 16, 1229-1236.
Meffert, M.K. Premack, B.A., and Schulman H. (1994). Nitric oxide stimulates calcium-independent synaptic vesicle release. Neuron 12, 1235-1244.
Meffert, M.K.*, Haley J.E.*, Schuman, E.M., Schulman, H., and Madison, D.V. (1994). Inhibition of hippocampal heme oxygenase, nitric oxide synthase and long-term potentiation by metalloporphyrins. Neuron 13, 1225-1233.