Ph.D., University of Utah 2005
Postdoctoral Fellow, University of Massachusetts Medical Center, 2005-2010
Dr. Speese earned a B.S. in biology from Clarkson University in Potsdam, NY (1998) and then went on to complete his Ph.D. (2005) at the University of Utah exploring mechanisms of synaptic transmission and modulation in Drosophila and C. elegans in the labs of Dr. Kendal Broadie and Dr. Erik Jorgensen. He then joined the lab of Dr. Vivian Budnik at the University of Massachusetts Medical School as a postdoctoral fellow. His work at UMASS led to the discovery of a novel mRNA export pathway that is critical for activity dependent synapse development at the Drosophila NMJ. In 2010 Dr. Speese came to the Jungers center as a Research Assistant Professor and in 2014 transitioned to the position of Assistant Professor. Dr. Speese continues to utilize the Drosophila NMJ to investigate mechanisms of synaptic function, formation and plasticity.
Synaptic Development, Function and PlasticityNeurons form elaborate synaptic connections with post-synaptic targets to establish complex circuits that regulate an organism’s behavior, cognition and plasticity. To meet these demands, neurons utilize elegant methods to temporally and spatially regulate gene expression including, activity-dependent signaling pathways linking synaptic activity to the nucleus, regulated RNA export, local protein degradation, RNA transport and local translation at the synapse. It is becoming increasingly clear that tight regulation of mRNA transcript localization and local translation is essential for the formation and function of the nervous system, and, interestingly, a number of RNA binding proteins which regulate various aspects of RNA metabolism in the cell have been linked to neurodevelopment and neurodegenerative diseases.
1) What molecular pathways control communication between the synapse and the nucleus?
2) Do these pathways regulate gene expression at the transcriptional and/or translation level?
3) What role does RNA transport and local translation play in synaptic outgrowth and maintenance?
4) How does synaptic activity regulate gene expression?
5) How do defects in nucleus to synaptic signaling mechanisms lead to human disease states.
We utilize the Drosophila larval neuromuscular junction (NMJ), which is a powerful in vivo genetic model to investigate conserved molecular mechanisms underlying synapse formation, function and plasticity. The larval NMJ is amenable to a wide array of visualization and manipulation techniques; we combine genetic and molecular approaches with multiple imaging modalities including, electron microscopy, confocal/super resolution, array tomography and live cell imaging methods to explore the molecular cascades and gene expression mechanisms that regulate motorneuron synapse development and function.
Frizzled Nuclear Import (FNI) and Nuclear Envelope Budding (NEB)Wnt/Wingless(Wg) signaling regulates synapse development and plasticity in the vertebrate brain and at the Drosophila NMJ. Work from our group and other labs have characterized a non-canonical Wnt/Wingless(Wg) synapse-to-nucleus signaling pathway, termed the Frizzled Nuclear Import (FNI) pathway (FIG 1), which regulates activity-dependent synapse formation at the neuromuscular junction (NMJ). In the FNI pathway, neuronal activity drives the release of the Wnt/Wg ligand from presynaptic boutons, which then binds Frizzled-2 (Fz2) receptors on the postsynaptic muscle. Following activation of the Fz2 receptor on postsynaptic muscle during NMJ development, the C-terminus of the Fz2 receptor (Fz2C) is liberated and imported into the nucleus, where it localizes to large granules (megaRNPs) that harbor mRNA messages encoding postsynaptic domain proteins (FIG 1&2). These megaRNPs are too large to exit the nucleus via the canonical nuclear pore complex, and instead utilize a novel nuclear export mechanism termed Nuclear Envelope Budding (NEB) (FIG 1), which is morphologically and molecularly similar to the nuclear egress of herpes virus capsids. We hypothesize that these megaRNPs will transport mRNA messages to the postsynaptic domain for local translation. We are actively exploring the mechanisms by which these megaRNPs form, are released from the nucleus, and then traffic within the postsynaptic muscle.
Figure 1 - Cartoon depiction of the Frizzled Nuclear Import (FNI) pathway and Nuclear Envelope Budding (NEB).
Figure 2 - Images of NEB and nuclear mega RNPs.
The role of glia in the healthy and diseased brain
We also have a number of ongoing projects in collaboration with the lab of Dr. Mary Logan (Jungers Center – OHSU) examining glial gene expression following axonal injury and the role of glia in regulating synaptic structure and function in the CNS. In addition, we are working on developing methods to image neuron-glial interaction in the CNS at high-resolution using various labeling technologies and imaging modalities (FIG 3).
Figure 3 - Comparison of conventional confocal microscopy and array tomography to resolve glial-synapse interactions in the adult Drosophila CNS.
Selected Relevant PublicationsSpeese SD, Ashley J, Nunnari J, Barria R, Jokhi V, Ataman B, Koon A, Chang Y, Li Q, Moore MJ, Budnik VB (2012) Nuclear envelope budding enables large ribonucleoprotein particle export during synaptic Wnt signaling. Cell 149:832-846.
Logan MA, Hackett R, Doherty J, Sheehan A, Speese SD, Freeman MR (2012) Negative regulation of glial engulfment activity by Draper and Corkscrew terminates glial responses to axon injury. Nat Neurosc 15:722-730.
Dialynas G, Speese S, Budnik V, Geyer PK, Wallrath LL (2010) The role of Drosophila Lamin C in muscle function and gene expression. Development 137: 3067-3077.
Speese SD, Petrie M, Schuske K, Ailion M, Ann K, Iwasaki K, Jorgensen EM, Martin TF (2007) UNC-31(CAPS) is required for dense core vesicle release but not synaptic vesicle exocytosis in Caenorhabditis elegans. J Neurosci 27:6150-6162.
Speese SD, Budnik V (2007) Wnts: up-and-coming at the synapse. Trends in Neurosci 30:268-275.
Speese SD, Trotta N, Rodesch CK, Aravamudan B, Broadie K (2003) The ubiquitin proteasome system acutely regulates presynaptic protein turnover and synaptic efficacy. Curr Biol 13:899-910.
Zhang YQ, Bailey AM, Matthies HJ, Renden RB, Smith MA, Speese SD, Rubin GM, Broadie K (2001) Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function. Cell 107:591-603.
BS, Portland State University 2014
I recently graduated with a degree in Micro/Molecular Biology from Portland State University. Science had always interested me as a child, and for a long time I imagined myself going in to medicine. After experiencing my first cadaver lab in freshman Biology, I reconsidered that choice. At Portland State I had a brief stint in Dr. Rahul Raghavan’s lab working to elucidate the evolutionary mechanisms that affect virulence in bacteria. Prior to my final year in college I came to work with Dr. Speese in the Jungers Center at OHSU, which became a full-time Research Assistant position after the completion of my degree. My primary roles in the lab include general maintenance of supplies and fly stocks, as well as performing experiments to shed light on potential components involved in the regulation of Nuclear Envelope Budding.