Kimberley R. Tolias, Ph.D.
Department of Neuroscience
Department of Biochemistry and Molecular Biology
Education and Awards
- Ph.D., Harvard Medical School, 1998
- 2005-2006 Children's Hospital Postdoctoral Career Development Fellowship
- 2002-2004 NIH Neuroscience Training Grant, Harvard Medical School
- 1999-2002 Damon Runyon Cancer Research Fellowship
- 1998-1999 NIH Hematology Training Grant, Harvard Medical School
- 1995-1998 Ryan Fellowship
Signaling mechanisms controlling brain development and plasticity
- Formation and remodeling of excitatory synapses
- Axonal and dendritic growth and guidance
- Directed cell migration
The human brain is composed of approximately one hundred billion neurons, which communicate with one another through specialized sites of contact called synapses. During development, neurons organize into functional circuits, which involves a number of steps including cell migration, the growth and targeting of axons and dendrites, and the selection of appropriate synaptic partners. Once these circuits are formed, they can be further refined by neuronal activity. Research in the Tolias laboratory is broadly focused on investigating the molecular and cellular mechanisms that control these different aspects of nervous system development and plasticity. In addition, we are interested in understanding how defects in these processes contribute to neurological disorders including mental retardation and autism.
Mechanisms regulating the formation and remodeling of excitatory synapses
In the brain, most excitatory synapses are located on small actin-rich protrusions called dendritic spines. Activity-dependent 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 associated with numerous brain disorders including mental retardation, mental illness and neurodegenerative diseases, suggesting that the formation and maintenance of spines are critical for normal cognitive function. A major goal of the research in our laboratory is to elucidate novel signal transduction pathways that enable extrinsic factors, such as neuronal activity, to guide the growth and remodeling of dendritic spines and their resident synapses. We are particularly interested in signaling pathways involving Rho GTPases, key regulators of the actin and microtubule cytoskeleton. Rho GTPases (e.g. Rac1, RhoA, and Cdc42) play important roles in regulating spine morphogenesis, and mutations in genes involved in Rho GTPase signaling cause X-linked mental retardation in humans. We previously identified the Rac1-specific activator Tiam1 as a critical mediator of NMDA receptor- and EphB receptor-dependent spine formation. Our results suggest that Tiam1 couples these receptors to spine and synapse development by inducing Rac1-dependent actin remodeling. To identify and characterize novel mediators of synapse development and plasticity, we are employing a diverse range of molecular, biochemical, and cell biological approaches. In addition, we use transgenic mice to explore the in vivo roles of these proteins in cognitive development and function.
Control of nervous system development and plasticity by Rho GTPase signaling pathways
As key regulators of cytoskeletal dynamics, Rho GTPases control many different aspects of nervous system development and plasticity in addition to synapse development. For instance, Rho GTPases direct neuron and astrocyte migration, axon growth and guidance, and dendritic arborization in response to extracellular cues. We are interested in determining how Rho GTPases and their regulatory proteins coordinate these different cellular processes during nervous development, plasticity, and following injury or disease. Results from our studies should provide insight into normal brain development and plasticity as well as neurological disorders such as mental retardation and autism.
- Tolias KF, Duman JG, Um K. Control of synapse development and plasticity by Rho GTPase regulatory proteins. Prog Neurobiol. 2011 Jul;94(2):133-48.
- Tolias KF, Bikoff JB, Kane CG, Tolias CS, Hu L, Greenberg ME. The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development. Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7265-70.
- Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, Segal RA. Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron. 2007 Jul 5;55(1):53-68.
- Tolias KF, Bikoff JB, Burette A, Paradis S, Harrar D, Tavazoie S, Weinberg RJ, Greenberg ME. The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines. Neuron. 2005 Feb 17;45(4):525-38.
- Saito K, Tolias KF, Saci A, Koon HB, Humphries LA, Scharenberg A, Rawlings DJ, Kinet JP, Carpenter CL. BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity. Immunity. 2003 Nov;19(5):669-78.
- Tolias K, Carpenter CL. In vitro interaction of phosphoinositide-4-phosphate 5-kinases with Rac. Methods Enzymol. 2000;325:190-200.
- Tolias KF, Carpenter CL. Enzymes involved in the synthesis of PtdIns-4,5-P2 and their regulation-PtdIns Kinases and PtdInsP Kinases. Biology of Phosphoinositides: Frontiers in Molecular Biology. 2000.
- Tolias KF, Hartwig JH, Ishihara H, Shibasaki Y, Cantley LC, Carpenter CL. Type Ialpha phosphatidylinositol-4-phosphate 5-kinase mediates Rac-dependent actin assembly. Curr Biol. 2000 Feb 10;10(3):153-6.
- Tolias KF, Couvillon AD, Cantley LC, Carpenter CL. Characterization of a Rac1- and RhoGDI-associated lipid kinase signaling complex. Mol Cell Biol. 1998 Feb;18(2):762-70.
- Tolias KF, Rameh LE, Ishihara H, Shibasaki Y, Chen J, Prestwich GD, Cantley LC, Carpenter CL. Type I phosphatidylinositol-4-phosphate 5-kinases synthesize the novel lipids phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 5-phosphate. J Biol Chem. 1998 Jul 17;273(29):18040-6.