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Karen A. Litwa, Ph.D.

Karen Litwa

Assistant Professor

office: Brody 7W-48A
telephone: 252-744-5555
email: litwak16@ecu.edu

B.S., Grove City College
Ph.D., Emory University
Postdoctoral Fellow, University of Virginia School of Medicine


Research

Our research focuses on brain development, specifically the molecular mechanisms that shape neuronal connections underlying diverse cognitive functions, from learning and memory formation to social abilities. We are also interested in how these mechanisms contribute to altered connectivity in neurodevelopmental disorders, such as Autism. In order to model these complex disorders, we use a physiologically relevant system, neurons derived from human induced pluripotent stem cells.

We focus on how neuronal connections, i.e. synapses, form and remodel in both development and in response to excitatory stimuli. The actomyosin cytoskeleton supports these changes in synaptic development. However, the mechanisms regulating actomyosin organization during development and in response to specific stimuli remain unclear. We are currently investigating the upstream regulators that orchestrate these changes in cytoskeletal organization. In particular, the Rho family of small GTPases (RhoGTPases) govern actomyosin activity and organization. RhoGTPase are activated by Guanine Exchange Factors (GEFs), inactivated by GTPase-Activating Proteins (GAPs), and further attenuated by Guanine Dissociation Inhibitors (GDIs). These pathways that regulate actomyosin organization are also commonly found in copy number variants and de novo mutations of neurodevelopmental disorders, such as Autism and schizophrenia. To identify potential therapeutic targets, it is necessary to determine when these RhoGTPase regulators act and to select those specific for discrete stages of neuronal development.

Our major research goals are: 1) To understand how these diverse RhoGTPase regulators act temporally during brain development. To accomplish this goal, we differentiate human induced pluripotent stem cells into neurons as both 2-D monolayers and 3-D organoids, allowing us to capture the stages of brain development from progenitor cell differentiation into neurons and supporting glial cells to cortical layer formation. We can then asses how acute genetic and pharmacologic regulation of RhoGTPase pathways affects these specific stages of brain development. 2) To determine how RhoGTPase regulators dynamically regulate synaptic RhoGTPase activity and subsequent actin cytoskeletal rearrangements associated with synapse formation and maturation. Our current research focuses on how PDZ domains within RhoGTPase regulators spatially restrict actomyosin organization, and the mechanisms by which excitatory stimulation affects the synaptic localization of RhoGTPase regulators to allow for actomyosin rearrangements that support synaptic strengthening. 3) To assess how myosin II-mediated actin rearrangements alter synaptic signaling. We have previously demonstrated that the actin motor protein, non-muscle myosin II, is necessary and sufficient to drive morphological synapse maturation (PMID: 21887379, 26169356). Using genetically encoded biosensors we can now determine how this myosin-II mediated activity spatially regulates signaling complex formation and subsequent excitatory stimulation at the synapse. Together, these proposed studies aim to advance our understanding of the precise spatial and temporal mechanisms that orchestrate brain development, and how these are altered in neurodevelopmental disorders.



Selected Publications

Salazar, G., B. Craige, M.L. Styers, K.A. Newell-Litwa, M.M. Doucette, B.H. Wainer, J.M. Falcon-Perez, E.C. Dell'Angelica,, A.A. Peden, E. Werner, and V. Faundez. 2006. BLOC-1 complex deficiency alters the targeting of adaptor protein complex-3 cargoes. Mol. Biol. Cell. 17: 4014-4026. PMID: 16760431

Newell-Litwa, K, E. Seong, M. Burmeister, and V. Faundez. 2007. Neuronal and non-neuronal functions of the AP-3 sorting machinery. J. Cell Sci. 120: 531-541. PMID: 17287392

Berger, A.C., G. Salazar, M.L. Styers, K.A. Newell-Litwa, E. Werner, R.A. Maue, A.H. Corbett, and  V. Faundez. 2007. The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3. J. Cell Sci. 120: 3640-3652. PMID: 17895371

Mumma, J.O., J.S. Chhay, K.L. Ross, J.S. Eaton, K.A. Newell-Litwa, and J.L. Fridovich-Keil. 2008. Distinct roles of galactose-1P in galactose-mediated growth arrest of yeast deficient in galactose-1P uridylyltransferase (GALT) and UDP-galactose 4'-epimerase (GALE). Mol. Genet. Metab. 93: 160-171. PMID: 17981065

Newell-Litwa, K., G. Salazar, Y. Smith, and V. Faundez. 2009. Roles of BLOC-1 and adaptor protein-3 complexes in cargo sorting to synaptic vesicles. Mol. Biol. Cell 20: 1441-1453. PMID: 19144828

Newell-Litwa, K., S. Chintala, S. Jenkins, J.K. Pare, L. McGaha, Y. Smith, and V.Faundez. 2010. Hermansky-Pudlak protein complexes, AP-3 and BLOC-1, differentially regulate presynaptic composition in the striatum and hippocampus. J. Neurosci. 30: 820-831. PMID: 20089890

Vicente-Manzanares, M., K. Newell-Litwa, A.I. Bachir, L.A. Whitmore, and A.R. Horwitz. 2011. Myosin IIA/IIB restrict adhesive and protrusive signaling to generate front-back polarity in migrating cells. J. Cell Biol. 193: 381-386. PMID: 21482721

Newell-Litwa, K. A. and A.R. Horwitz. 2011. Cell migration: PKA and RhoA set the pace. Curr. Biol. 21: R596-R598. PMID: 21820627

Hodges, J. L., K. Newell-Litwa, H. Asmussen, M. Vicente-Manzanares, and A.R. Horwitz. 2011. Myosin IIB activity and phosphorylation status determines dendritic spine and post-synaptic density morphology. PLOS One 6: e24149. PMID: 21887379

Newell-Litwa, K., M. Badoual, H. Asmussen, H. Patel, L. Whitmore, and A.R. Horwitz. 2015. ROCK1 and 2 differentially regulate actomyosin organization to drive cell and synaptic polarity. J. Cell Biol. 210: 225-242. PMID: 26169356

Newell-Litwa, K., A.R. Horwitz, and M.L. Lamers. 2015. Non-muscle myosin II in disease: mechanisms and therapeutic opportunities. Dis. Models Mech. 8: 1495-1515. PMID: 26542704

Newell-Litwa, K. 2016. Breaking down to build up: neuroligin's C-terminal domain strengthens the synapse. J. Cell Biol. 212:375-377. PMID: 26880198

Martin-Vilchez, S., L. Whitmore, H. Asmussen, J. Zareno, R. Horwitz, and K. Newell-Litwa. 2017. RhoGTPase regulators orchestrate distinct stages of synaptic development. PLoS One 12: e0170464. PMID: 28114311

View PubMed Publications for further listings


Staff and Students

Location 7W-52

Name Title Phone Email
Breanna Alligood Undergraduate Student 252-744-3671 alligoodb17@students.ecu.edu
Storm Davis Undergraduate Student 252-744-3671 daviss17@students.ecu.edu
Colin Johnson Undergraduate Student 252-744-3671 johnsonc16@students.ecu.edu
Brenna Kirk Research Technician 252-744-3671 owensa15@ecu.edu
Adrienne Orbita Undergraduate Student 252-744-3671 orbitaa15@students.ecu.edu
Pranaya Pakala Undergraduate Student 252-744-3671 pakalap16@students.ecu.edu
Alexis Papariello Graduate Student 252-744-3671 paparielloa16@students.ecu.edu
Amanda Petritsch Graduate Student 252-744-3671 petritscha16@students.ecu.edu
Taylor Rudisill Graduate Student 252-744-3671 rudisillt12@students.ecu.edu
Kinsley Tate Graduate Student 252-744-3671 morgankins13@students.ecu.edu
Emily Wilson Graduate Student 252-744-3671 wilsonemi16@students.ecu.edu