Background
Dr. Mollie Meffert is an associate professor of biological chemistry and neuroscience at the Johns Hopkins University School of Medicine. Her research focuses on the regulation of neuronal gene expression in health and disease. Dr. Meffert currently serves as the Vice Director of the Department of Biological Chemistry.
Research Description
The Meffert lab investigates mechanisms underlying enduring change in mammalian nervous system function in health and disease. We are interested in how cells in the nervous system make decisions to turn genes on or off, and how those decisions are remembered in processes such as development or plasticity, and in injury or disease. The goal of the Meffert lab is to gain a mechanistic understanding of how selective gene programs are recruited and maintained to alter synaptic, neuronal, and cognitive function. Rather than focusing on single genes, we investigate the upstream processes that allow coordinate regulation of many genes to achieve biological impact. Cell-specific and subcellularly localized posttranscriptional control by RNA-binding proteins and noncoding RNAs is an ongoing focus.
Our laboratory elucidated a post-transcriptional mechanism capable of organizing pro-growth gene programs in which activity-dependent regulation of microRNA (miRNA) production governs the selection of gene targets for protein synthesis. An RNA-binding protein, Lin28, is one activity-responsive factor that promotes pro-growth protein synthesis by downregulating only select miRNAs (e.g. the family of let-7 ‘growth-suppressor’ miRNAs), which repress pro-growth genes. In neurons, pro-growth mRNA targets of the let-7 miRNAs include mRNA for proteins involved in excitatory synaptic function, as well as growth, metabolism, and repair. In recent work, we develop discovery-based sequencing strategies to reveal in vivo small RNA targets through the production of small RNA:target chimeric molecules.
Dr. Meffert’s work has been recognized with awards including the: March of Dimes research scholar, Simons Foundation Autism Research Initiative award, PLU Rho Award, Alfred P. Sloan Research Fellow Award, Hamilton Smith Award for Innovative Science, and The Sontag Foundation Distinguished Scientist and Distinguished Alumni Awards.
Dr. Meffert and her laboratory are the current recipients of the Eric C. Aker Award Endowment through the Braude Foundation.
Expertise
Dr. Meffert received her undergraduate degree (BS) from Stanford University. She earned her MD/PhD in neuroscience from Stanford University School of Medicine and completed a postdoctoral fellowship at California Institute of Technology with Dr. David Baltimore.
Areas of research expertise in Dr. Meffert’s laboratory include molecular neuroscience, RNA biology, and gene expression. Her laboratory uses tools of molecular diagnostics, biochemistry, computational biology, quantitative imaging, and mouse and human genetic models of disease
Lab Members
Xinbei Li (BC graduate student), Bonita Powell (BCMB graduate student), Emily Eiss (BCMB graduate student), Ariella Kornfeld (BCMB graduate student), Sydney Pettit (BCMB graduate student), Preksha Jerajani (research technician), Anselmo Rivera (Hopkins undergraduate)
Selected Publications
- Xinbei Li, William T. Mills IV, Daniel S. Jin, and Mollie K.Meffert. (2024), Genome-wide and cell-type-selective profiling of in vivo small noncoding RNA:target RNA interactions by chimeric RNA sequencing. Cell Reports Methods, 4, 100836.
- Megha Subramanian, William T. Mills IV, Manish D Paranjpe, Uche Onuchukwu, Manasi Inamdar, Amanda R. Maytin, Xinbei Li, Joel L. Pomerantz, and Mollie K.Meffert. (2023), Growth suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency. iScience, 27 (1) 108676.
- William T. Mills IV, Sreenivas Eadara, Andrew E. Jaffe, and Mollie K. Meffert. (2022), SCRAP: a bioinformatic pipeline for the analysis of small chimeric RNA-seq data. RNA 29 (1); 1-17.
- Alexandra M Amen, Claudia R. Ruiz, Jay Shi, Megha Subramanian, Daniel Pham, and Mollie K. Meffert, (2017) A rapid induction mechanism for Lin28a in trophic responses. Molecular Cell, 65 (3); 490 – 503.
- Erica C. Dresselhaus, Matthew C. Boersma, and Mollie K. Meffert, (2018), Targeting of NF-kB to dendritic spines is required for synaptic signaling and spine development. J.Neurosci., 8(17); 4093-4103. PMID 29555853.
- Laurel M. Oldach, Kirill Gorshkov,William T. Mills, Jin Zhang*, and Mollie Meffert* (2018), A biosensor for MAPK-dependent Lin28 signaling. Molecular Biology of the Cell, 29(10), 1157-1167. PMID29540527.
- Yu-Wen A. Huang*, Claudia R. Ruiz*, E.C.H. Eyler*, Kathie Lin, and Mollie K. Meffert. “Dual regulation of miRNA biogenesis generates target specificity in neurotrophin-induced protein synthesis.” Cell, 148(5); 933-946. 2012.
Background
Dr. Seth Shatkin Margolis is an Associate Professor in the Department of Biological Chemistry with a Secondary appointment in the Sol Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine. Dr. Margolis and his research team are focused on studying the protein homeostasis machinery (protein translation and protein degradation) that control neuronal function in development and disease.
In 2017, Dr. Margolis and his team discovered a novel neuronal specific proteasome complex and a unique class of extracellular signaling peptides that it produces.
Dr. Margolis received his undergraduate degree in biochemistry from the University of Rochester and earned his Ph.D. from Duke University. He completed postdoctoral training in neurobiology at Harvard Medical School. Dr. Margolis joined the Johns Hopkins faculty in 2011.
Centers and Institutes
Basic Biomedical Sciences, Institute for
Recent News Articles and Media Coverage
- Seth Margolis on never underestimate the learning potential of a failed experiment
- Neural Connections
- Having It All, Johns Hopkins-Style
- Protein Besides Amyloid Beta Linked to Alzheimer’s Memory Problems, Alzheimer’s News Today (March 29, 2017)
- From Garbage Disposal to Neuromodulation? Membrane Proteasomes Churn Out Stimulating Peptides, Alzforum (March 17, 2017)
Additional Academic Titles
Associate Professor of Neuroscience
Research Interests
Formation and Function of the Neuronal Membrane Proteasome, Neuronal Survival and Neurodegeneration, Proteostasis
Lab Website
Margolis Lab – Lab Website
Projects in The Margolis Laboratory:
Proteasomes are essential for proper neuronal function. Since 2011 we have been focused on studying protein degradation in the nervous system. In 2017, we published on our new discovery of a neuronal specific proteasome complex and its link to neuronal function. Based on extensive original findings in the Margolislaboratory, our central hypothesis is that neuronal activity promotes the degradation of newly synthesized proteins through a membrane associated 20S proteasome complex in order to rapidly generate biologically meaningful peptides that may be critical for normal nervous system function. Nothing is known about this new form of rapid neuronal communication and further understanding is critical in providing vital insight into activity-dependent neuronal functions mediated by protein degradation. In addition, relevant tools are needed to control neuronal subtype specific NMP peptide-receptor signaling to bring this pathway closer to modern day neuroscience approaches. Given the critical importance of protein degradation to human health, the long-range objective of our research is to understand the regulation and function of this degradation program and to apply this knowledge to the detection and eventual treatment of cognitive disorders. Among other projects we aim to accomplish the following:
- To identify and study specific NMP peptide-receptor interactions relevant to neuronal signaling
- To identify and study molecular components required for NMP complex assembly
- To investigate the NMP as a regulator of neuronal function and physiology ex vivo and in vivo
Research Summary
Dr. Margolis has a broad background and expertise in using biochemical, proteomic, molecular cellular, mouse genetic, and behavior approaches to dissect protein homeostasis signaling mechanisms in neuronal biology. Over the years Dr. Margolisand his team has focused the laboratories efforts toward the ubiquitin proteasome pathways and actin cytoskeleton control of early developmental excitatory synapse formation in healthy and diseased brain states. They have spent considerable effort investigating the functions of an ubiquitin ligase, UBE3A in neural development and its role in the human cognitive disorder Angelman syndrome. Specifically, they have been identifying the substrates of UBE3A that are targeted for proteasome-mediated degradation. UBE3A itself and at least one of these substrates is relevant to Alzheimer’s disease. They have since aimed part of our efforts to advancing an understanding of protein degradation mechanisms relevant to Alzheimer’s disease (AD) etiology.
In the course of their studies, Dr. Margolis and his team made an unexpected discovery which was built logically on the laboratories long standing interests. In short, they discovered a novel neuronal specific membrane associated proteasome complex that through extracellular proteasome-derived peptides modulates neuronal signaling. This system is contributes to activity dependent neuronal signaling and is disrupted in disease. The robustness, uniqueness, and reproducibility have kept them moving forward in order to generate significant future advances in tools and information to comprehend the role of this signaling in the nervous system both in health and disease. In the long term, Dr. Margolis envisions the lab following these pathways to address the following questions:
- What are the substrates of this proteasome complex and the sequences of the signaling peptides?
- How do these NMP derived peptides mediate their signaling capacity and specificity?
- What is the full make up of the neuronal membrane proteasome (NMP) complex and how is it regulated?
- What is the importance of this pathway to neuronal physiology and animal behavior in health and disease?
They hope to leverage their findings in order to better define this emerging field and provide the tools and information important for their research and the field of cellular and molecular neuroscience as a whole.
Selected Publications
- Ramachandran KV, Margolis SS. A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function. Nat Struct Mol Biol. (2017) Apr;24(4):419-430. doi: 10.1038/nsmb.3389.
- Ramachandran KV, Fu JM, Schaffer TB, Na CH, Delannoy M, Margolis SS. Activity-Dependent Degradation of the Nascentome by the Neuronal Membrane Proteasome. Mol Cell. (2018) Jul 5;71(1):169-177.e6. doi: 10.1016/j.molcel.2018.06.013.
- Schaffer TB, Smith JE, Cook EK, Phan T, Margolis SS. PKCε Inhibits Neuronal Dendritic Spine Development through Dual Phosphorylation of Ephexin5. Cell Rep. (2018) Nov 27;25(9):2470-2483.e8. doi: 10.1016/j.celrep.2018.11.005.
- Sell GL, Schaffer TB, Margolis SS. Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer’s-like impairment in mice. J Clin Invest. (2017) May 1;127(5):1646-1650. doi: 10.1172/JCI85504.
Graduate Program Affiliations
- Graduate Program in Biochemistry, Cell, and Molecular Biology
- Graduate Program in Neuroscience
- Graduate Program in Biological Chemistry
Professional Activities
- Basic Science Institute Summer Internship Program (BSI-SIP), Co-Director and Admissions Committee
- BCMB Graduate Admissions Committee, 2019, Member,
- BCMB Graduate Program Retreat,, Co-Director,, 1/1/13
- Faculty Senate, Representative for Department of Biological Chemistry
- XDBio Graduate Program, Advisory Board
Additional Training
Postdoctoral Training, Harvard Medical School, Boston, MA, 2011, Neurobiology
Affiliation: Solomon H. Snyder Professor of Neurosurgery, Professor of Biological Chemistry, Professor of Neuroscience
Director, Department of Biological Chemistry
Director, Neurosurgery Pain Research Institute
Description of Research
The Caterina lab studies mechanisms underlying neuropathic and inflammatory pain, predominantly using mice as a model system. We employ a wide array of methods, including mouse pain behavioral assays, sensory neuroanatomy, in vitro and in vivo neuronal imaging and electrophysiology, cell culture, biochemistry, transcriptomic analysis, and CAS9/Crispr mouse mutagenesis. Through the complementary application of these approaches, and in collaboration with multiple laboratories (e.g., Meffert, Gould, Margolis), we seek to understand the cell types and molecules that contribute to the pathological sensation of pain, with the goal of guiding improvements in pain therapy.
Pain Mechanisms in Hereditary Palmoplantar Keratodermas
Hereditary Palmoplantar Keratodermas (PPK) are a heterogeneous group of rare disorders characterized by thickening of the epidermis on the palms of the hand and soles of the feet. Mutations in any of at least 25 different genes can result in PPK. In some, but not all patients with hereditary PPK, pain at the site of lesions is a prominent symptom, and is very difficult to treat. Using mouse models of human hereditary PPKs, we seek to identify specific molecular and cellular mechanisms that lead to enhanced pain sensitivity in PPK lesions. Through these efforts, we hope to identify therapeutic targets for improved treatment of pain in PPK and also to define novel mechanisms that might be relevant to other, more common pain disorders.
Cellular and Molecular Mechanisms of Neuropathic Pain
Peripheral nerve injury, whether due to traumatic, metabolic, infectious, or toxic causes, often results in abnormally enhanced pain sensitivity known as neuropathic pain. Using an array of surgical nerve injury models, we seek to understand the complex interplay between injured neurons, uninjured neurons, and nonneuronal cells (e.g. immune cells, keratinocytes, glial cells) that produce neuropathic pain and to understand how the processes of nerve regeneration and collateral sprouting, two additional consequences of nerve injury, influence and are influenced by pathological pain mechanisms.
Synthetic Biology Approaches to Treat Pathological Pain
One hallmark of many inflammatory and neuropathic pain mechanisms is an imbalance between signal transduction pathways that augment the sensitivity of nociceptive neurons and those that attenuate that sensitivity. Using a synthetic biology approach, we are seeking to develop genetically encoded “smart” systems that produce analgesia only during times of excess pro-nociceptive signaling. These systems, which are triggered by common pathological signaling processes such as receptor tyrosine kinase hyperfunction or elevated intracellular calcium, may prove beneficial not only in the setting of pathological pain but also in other disease states where such pathways are hyperactive.
Lab Members:
- Dr. Sangmin Jeon (Assistant Professor)
- Dr. Dennis Chang (Postdoctoral Fellow)
- Suyeon Kim (PhD student)
- Yijing Gong (PhD student)
- Austin Dabbs (PhD student)
- Trupti Tripathi (PhD student)
- Lanzhuo Wu (MS student)
- Stella Du (MS student)
- Jahnavi Gupta (Research Specialist)
- Matthew Russell (Research Technologist)
Recent Publications:
- Weinberg R.L.*, Kim S.*, Pang Z., Awad S., Hanback T., Pan B., Bettin L., Chang D., Polydefkis M.J., Qu L., Caterina M.J. Pain Hypersensitivity in Slurp1 and Slurp2 Knockout Models of Hereditary Palmoplatar Keratoderma. Under revision for J Neuroscience.*Denotes equal contributions
- Jeon S.M.*, Pradeep A., Chang, D., McDonough L., Chen Y., Latremoliere A., Crawford L.K., and Caterina M.J. Skin Reinnervation by Collateral Sprouting Following Spared Nerve Injury in Mice. Accepted, J. Neuroscience *Denotes communicating author. (also presented as bioRxiv. 2023 Sep 13:2023.09.12.557420. doi: 10.1101/2023.09.12.557420. Preprint.PMID: 37745384)
- Li X., Jin D.S., Eadara S., Caterina M.J., and Meffert M.K. (2023) Regulation by Noncoding RNAs of Local Translation, Injury Responses, and Pain in the Peripheral Nervous System Neurobiology of Pain, Jan 24:13:100119. doi: 10.1016/j.ynpai.2023.100119.
- Beauchene C., Zurn C.A., Eherns, D., Duff I., Duan W., Caterina M., Guan Y., Sarma S.V. (2022) Steering Towards Normative Wide-Dynamic-Range Neuron Activity in Nerve-Injured Rats with Closed-Loop Peripheral Nerve Stimulation. Neuromodulation: Technology at the Neural Interface. 2022 Nov 16:S1094-7159(22)013290. PMID: 36402658
- Liu U., Caterina M.J., and Qu, L. (2022) Sensory Neuron Expressed FcγRI Mediates Postinflammatory Arthritis Pain in Female Mice Front Immunol. 2022 Jun 27;13:889286. doi: 10.3389/fimmu.2022.889286. PMID: 35833115
- Liu Y, Liu Y, Limjunyawong N, Narang C, Jamaldeen H, Yu S, Patiram S, Nie H, Caterina MJ, Dong X, Qu L. (2022) Sensory neuron expressed TRPC3 mediates acute and chronic itch. Pain. 2022 May 4. doi: 10.1097/j.pain.0000000000002668. PMID: 35507377
- Liu Y, Jeon SM, Caterina MJ, Qu L. (2021) miR-544-3p mediates arthritis pain through regulation of FcγRI. Pain. 2021 Nov 12. doi: 10.1097/j.pain.0000000000002531. Online ahead of print.PMID: 34784311 (also presented as bioRxiv 2021.06.13.448256; doi: https://doi.org/10.1101/2021.06.13.448256)
- Xu Q., Ford N.C., He S., Huang Q., Anderson M., Chen Z., Yang F., Crawford L.K., Caterina M.J., Guan Y., and Dong X. (2021) Astrocytes contribute to pain gating in the spinal cord Sci Adv. 2021 Nov 5;7(45):eabi6287. doi: 10.1126/sciadv.abi6287. Epub 2021 Nov 3.PMID: 34730998
- Li X., Eadara S., Jeon S. Liu Y., Muwanga G., Qu L., Caterina M.J., and Meffert, M.K. (2021) Combined single-molecule fluorescence in-situ hybridization and immunohistochemistry analysis in intact dorsal root ganglia and sciatic nerve. STAR Protoc. 2021 Jun 3;2(2):100555. doi: 10.1016/j.xpro.2021.100555. eCollection 2021 Jun 18.PMID: 34142098
- Jeon, S.*, Chang, D.*, Geske, A., Ginty, D.D., and Caterina, M.J. (2021) Sex-Dependent Reduction in Mechanical Allodynia in the Sural-Sparing Nerve Injury Model in Mice Lacking Merkel Cells. J Neurosci. 2021 Jun 30;41(26):5595-5619. https://pubmed.ncbi.nlm.nih.gov/34031166/.*Denotes equal contributions
- Weinberg R.L., Polydefkis M., Coulombe P.A., and Caterina M.J. Pain mechanisms in hereditary palmoplantar keratodermas (2020) Br. J. Dermatol. 182(3):543-551. PMID:30883689 https://pubmed.ncbi.nlm.nih.gov/30883689/
- Joseph J., Qu L., Wang S., Kim M., Bennett D., Ro J., Caterina M., and Chung M.K. (2019) Phosphorylation of TRPV1 S801 contributes to modality-specific hyperalgesia in mice J. Neuroscience Dec 11;39(50):9954-9966. https://pubmed.ncbi.nlm.nih.gov/31676602/
- Ostrow, K., Donaldson K.J., Caterina M.J., Belzberg A., and Hoke A. (2019) The Secretomes of Painful Versus Nonpainful Human Schwannomatosis Tumor Cells Differentially Influence Sensory Neuron Gene Expression and Sensitivity Scientific Reports Sep 11;9(1):13098
- Wang L., Jiang X., Zheng Q., Jeon S.M., Chen T., Kulaga H., Reed R., Dong X., Caterina M.J., and Qu L. (2019) Neuronal FcgRI mediates acute and chronic joint pain through a noninflammatory mechanism J Clin Invest. Jun 18;130:3754-3769. PMID:31211699
- A more extensive list of publications can be found at https://www.ncbi.nlm.nih.gov/myncbi/1XyKtr6en1Y50/bibliography/public/