Mollie K. Meffert
725 N. Wolfe Street
413 Physiology Building
Baltimore MD 21205
How are gene programs regulated to modify the brain during experience and disease?
The Meffert lab studies molecular mechanisms underlying enduring changes in brain function. We are interested in understanding how programs of gene expression are coordinated and maintained to mediate altered synaptic, neuronal, and cognitive performance. Rather than concentrating on single genes, our research is particularly focused on understanding the upstream processes that allow stimuli to synchronously orchestrate both up and down-regulation of the many genes required to mediate changes in growth and excitation. This process of gene target specificity is implicit to the appropriate production of gene expression programs that control lasting alterations in brain function.
Advances in sequencing and proteomics have revealed that post-transcriptional regulation of gene expression plays a predominant role in determining the cellular complement of proteins, but knowledge of post-transcriptional mechanisms capable of coordinating growth programs in neurons or locally at synapses has been lacking. Our laboratory elucidated a mechanism responsible for pro-growth programs of protein synthesis in which activity-dependent regulation of microRNA (miRNA) production governs the selection of gene targets for protein synthesis. We found that the translating pool of RNA may be controlled through both positive and negative regulation of the biogenesis of mature microRNA from precursor microRNAs. Our laboratory is further exploring the importance of microRNA biogenesis and RNA-binding proteins 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, as well as peripheral nociceptive responses.
Disruption in the growth and function of synaptic connections is a central feature in the development of multiple cognitive disabilities, including autism spectrum disorder. While our understanding of how brain development differs in autism is far from cohesive, an early overgrowth of neurons and synaptic contacts, as well as a failure to prune inappropriate synapses, has been observed in children with autism and in several mouse models of autism. At the molecular level, accumulated evidence indicates that dysregulated protein synthesis, resulting in overproduction of key synaptic proteins, contributes to atypical neural and synaptic growth in autism. Ongoing studies in our laboratory are using mouse models and human samples to investigate how protein synthesis and microRNA biogenesis may be pathologically regulated to produce an overabundance of pro-growth proteins and behavioral features in autism.
A second major focus of our laboratory investigates how target specificity is generated in response to neuronal stimuli that regulate protein synthesis. Videos showing increased mRNA repression (RNA-processing bodies) in live neurons responding to BDNF: Messenger RNA accumulates in a neuron BDNF-treated neuron.
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 mouse models and techniques of molecular biology, cell biology, biochemistry, high-throughput expression analysis and bioinformatics, virology, histology, high resolution cellular imaging, mouse genetics and behavior. Neuronal gene products of interest include both proteins and non-coding RNAs.
Oldach,L.M., Gorshkov, K., Mills, W.T., Zhang J.*, and Meffert M.K*, (2018), A biosensor for MAPK-dependent Lin28 signaling. Molecular Biology of the Cell, 29(10), 1157-1167.
Dresselhaus, E.C., Boersma, M.C., and Meffert, M.K, (2018), Targeting of NF-kB to dendritic spines is required for synaptic signaling and spine development. J.Neurosci., 8(17); 4093-4103.
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.