Associate Professor, Baylor College of Medicine
Ph.D., Harvard Medical School, 1998
Molecular signaling pathways in structural development and plasticity of dendrites and synapses
The goal of our research is to understand the molecular and cellular mechanisms that control synapse development and plasticity, and to determine how defects in these processes contribute to neurological disorders. Most excitatory synapses in the mammalian brain are located on actin-rich protrusions called dendritic spines. Changes in the shape, density, and protein composition of spines are thought to be important for processes such as learning and memory. Furthermore, spine abnormalities are frequently associated with brain disorders including mental retardation and mental illness, raising the possibility that the formation and maintenance of spines is critical for normal cognitive function. Research in the laboratory is focused on elucidating novel signal transduction pathways that enable extrinsic factors, such as neuronal activity, to guide the growth and remodeling of spines.
We are particularly interested in signaling pathways involving Rho family GTPases, key regulators of the actin cytoskeleton. Rho GTPases (including Rac1, RhoA, and Cdc42) are known to play important roles in spine morphogenesis, and mutations in genes involved in Rho GTPase signaling cause X-linked mental retardation in humans. Recently, we identified the Rac1-activator Tiam1 as a critical mediator of NMDA receptor-dependent spine formation. Our results suggest that Tiam1 promotes spine development in response to NMDA receptor stimulation by inducing Rac1-dependent actin remodeling and protein synthesis. To identify and characterize novel mediators of synapse development and plasticity, we will employ molecular, biochemical, and cell biological approaches including confocal microscopy, RNA interference, and mass spectrometry. In addition, we will use transgenic mice to explore the in vivo functions of these proteins in cognitive development. Results from these studies should provide insight into learning and memory as well as neurological disorders such as mental retardation and autism.
Tolias KF, Hartwig JH, Ishihara H, Shibasaki Y, Cantley LC, Carpenter CL (2000) Type Ialpha phosphatidylinositol-4-phosphate 5-kinase mediates Rac-dependent actin assembly. Current Biology 10:153-156.
Tolias KF, Carpenter CL (2000) Enzymes involved in the synthesis of phosphatidylinositol 4,5 bisphosphate and their regulation – Phosphoinositide kinases. In Biology of Phosphoinositides: Frontiers in Molecular Biology 27.
Tolias KF, Carpenter CL (2000) In vitro interaction of phosphoinositide-4-phosphate 5-kinases with Rac. Methods in Enzymology 325:190-200.
Saito K, Tolias KF, Saci A, Koon HB, Humphries LA, Scharenberg A, Rawlings DJ, Kinet JP, Carpenter CL (2003) BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity. Immunity 19:669-678.
Tolias KF, Bikoff JB, Burette A, Paradis S, Harrar D, Tavazoie S, Weinberg RJ, Greenberg ME (2005) The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines. Neuron 45:525-538.
Tolias KF, Bikoff JB, Kane CG, Tolias CS, Hu L, Greenberg ME (2007) The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development. Proceedings of the National Academy of Sciences USA 104:7265-7270.
Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, Segal RA (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55:53-68.
Tolias KF, Duman JG, Um K (2011) Control of synapse development and plasticity by Rho GTPase regulatory proteins. Progress in Neurobiology 94:133-148.
Schwechter B, Rosenmund C, Tolias KF (2013) RasGRF2 Rac-GEF activity couples NMDA receptor calcium flux to enhanced synaptic transmission. Proceedings of the National Academy of Sciences USA 110:14462-14467.
Duman JG, Tzeng CP, Tu YK, Munjal T, Schwechter B, Ho TS, Tolias KF (2013) The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites. Journal of Neuroscience 33:6964-6978.
Reyes SB, Narayanan AS, Lee HS, Tchaicha JH, Aldape KD, Lang FF, Tolias KF, McCarty JH (2013) αvβ8 integrin interacts with RhoGDI1 to regulate Rac1 and Cdc42 activation and drive glioblastoma cell invasion. Molecular Biology of the Cell 24:474-482.
Kimberley R. Tolias, Ph.D.
Department of Neuroscience
Baylor College of Medicine
One Baylor Plaza S607B
Houston, Texas 77030, U.S.A.
Tel: (713) 798-3981
Fax: (713) 798-3946