Kevin Wright, Ph.D.
After earning his B.S. in Neuroscience from Allegheny College in 2001, Kevin received his Ph.D. in Neurobiology from The University of North Carolina, Chapel Hill in 2006. He did his postdoctoral training at Johns Hopkins Medical Institute. In 2013 he was appointed as an assistant scientist at the Vollum Institute.
Summary of Current Research
During development, neurons from distinct areas of the nervous system connect to one another to form functional circuits. Neurons must interpret a complex environment of extracellular cues in order to migrate to their final location, extend axons to the correct target fields, develop dendritic arbors with complex architectures, and form synapses with their appropriate targets. Our lab utilizes genetic, molecular and biochemical approaches in order to identify the molecular pathways that govern these processes and to understand how they are affected in various neurological disorders
The developing sensory-spinal circuit is comprised of the primary sensory neurons of the dorsal root ganglia (DRG) and their second-order targets in the spinal cord and brainstem. Within the DRG there are several genetically distinct subtypes of neurons that convey specific sensory stimuli from the periphery to the spinal cord and brainstem. The peripheral axons from each of these sensory neuron subtypes form unique, specialized terminal arborizations, while the centrally projecting axons exhibit distinct, stereotypical branching patterns and target specific lamina within the spinal cord. These features make the sensory-spinal circuit an ideal model system for studying the mechanisms that govern neuronal differentiation, migration, axon guidance, laminar targeting, dendritic arborization and synaptogenesis.
To identify the molecular pathways required for sensory-spinal circuit formation, we are taking both open-ended and candidate genetic approaches. We previously conducted a forward genetic mutagenesis screen in mice in order to identify genes required for normal neural circuit development. As part of this screen, we identified a critical role for the extracellular matrix (ECM) protein dystroglycan in regulating axon tract formation during the development of the sensory-spinal circuit. We found that dystroglycan organizes the basement membrane surrounding the spinal cord into an ECM-rich permissive growth substrate for developing axons, while also directly binding the repulsive axon guidance cue Slit to regulate its localization in the extracellular environment.
One of the ongoing projects in the lab is an investigation into the role of dystroglycan in regulating axonal tract formation, dendritic arborization, and synapse formation and function throughout the developing nervous system. This work has direct clinical implications, as human patients with mutations that affect dystroglycan function develop a form of congenital muscular dystrophy that is often accompanied by significant neurodevelopmental defects. In addition to our work on dystroglycan, we are continuing to analyze several uncharacterized mutant lines from the forward genetic screen to identify novel molecular pathways that govern neural development.
We are also interested in exploring the molecular basis for how genetically distinct subtypes of neurons respond differentially to cues in the extracellular environment to form functional neural circuits. To better understand how this occurs, we are using novel genetic tools that allow us to label and manipulate specific subtypes of sensory neurons in combination with molecular and proteomic approaches to identify candidate molecules responsible for the unique axonal branching patterns, laminar targeting and choice of synaptic partners.
Wright KM, Lyon K, Leung H, Leahy DJ, Ma L, Ginty DD (2012) Dystroglycan organizes axon guidance cue localization and axonal pathfinding. Neuron 76:931-944.
Charoy C, Nawabi H, Reynaud F, Derrington E, Bozon M, Wright K, Falk J, Helmbacher F, Kindbeiter K, Castellani V. (2012) GDNF activates midline repulsion by Semaphorin3B via NCAM during commissural axon guidance. Neuron 75:1051-1066.
Merte J, Jensen D, Wright K, Sarsfield S, Wang Y, Schekman R, Ginty DD. (2009) Sec24b selectively sorts Vangl2 to regulate planar cell polarity during neural tube closure. Nature Cell Biol 12:41-46.
Johnson CE, Huang YY, Parrish AB, Smith MI, Vaughn AE, Zhang Q, Wright KM, Van Dyke T, Wechsler-Reya RJ, Kornbluth S, Deshmukh M. (2007) Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues. Proc Natl Acad Sci 104:20820-20825.
Wright KM, Smith MI, Farrag L, Deshmukh M. (2007) Chromatin modification of Apaf-1 restricts the apoptotic pathway in mature neurons. J Cell Biol 179:825-832.
Wright KM, Vaughn AE, Deshmukh M. (2007) Apoptosome dependent caspase-3 activation pathway is non-redundant and necessary for apoptosis in sympathetic neurons. Cell Death Differ 14:625-633.
Wright KM, Deshmukh M. (2006) Restricting apoptosis for postmitotitc cell survival and its relevance to cancer. Cell Cycle 5:1616-1620.
Schafer ZT, Parrish AB, Wright KM, Margolis SS, Marks JR, Deshmukh M, Kornbluth S. (2006) Enhanced sensitivity to cytochrome c induced apoptosis mediated by PHAPI in breast cancer cells. Cancer Research 66:2210-2218.
Wright KM, Linhoff MW, Potts PR, Deshmukh M. (2004) Decreased apoptosome activity with neuronal differentiation sets the threshold for strict IAP regulation of apoptosis. J Cell Biol 167:303-313.