Mollie Meffert MD, Ph.D
Telephone Number: 410-502-2570
Fax Number: 410-955-5759
School of Medicine
725 North Wolfe St.
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.
Recent links to our work:
Neuroscience Innovations http://neuroscience.jhu.edu/Meffert2012CellPaper.htm
Videos showing increased mRNA repression (RNA-processing bodies) in live neurons responding to BDNF:
Dual regulation of miRNA biogenesis generates target specificity in neurotrophin-induced protein synthesis.
Control of protein synthesis is a fundamental mechanism used by neurons to rapidly alter cellular and synaptic protein content in response to stimulation. The induction of protein synthesis by brain-derived neurotrophic factor (BDNF) critically contributes to enduring modifications of synaptic function, but how BDNF selectively affects only a minority of expressed mRNAs is poorly understood. This study by Huang et al. shows that specificity in BDNF-regulated translation depends upon a two-part post-transcriptional control of the biogenesis of microRNA (miRNA): mRNA repression by miRNA is generally enhanced (through BDNF-induction of Dicer), while specific mRNAs are selectively de-repressed and undergo increasing translation (through BDNF-induction of Lin28a).