Formation of a functional nervous system requires the proper development and remodeling of dendrites and dendritic spines, the primary sites of excitatory synapses in the brain. Rho family GTPases play critical roles in regulating these processes. In particular, the Rho GTPase Rac promotes dendritic arborization and the formation and maintenance of spines. Precise spatio-temporal regulation of Rac activity is essential for its function, since aberrant Rac signaling results in dendrite and spine abnormalities and cognitive disorders including mental retardation. Despite its importance, the mechanisms that regulate Rac signaling in neurons remain poorly understood. We previously identified the Rac-specific activator Tiam1 as a critical regulator of dendrite, spine, and synapse development. We demonstrated that Tiam1 mediates both NMDA receptor- and EphB receptor-dependent spine development by coupling these receptors to Rac signaling pathways that control actin cytoskeletal remodeling and protein synthesis. Recently, we have also identified the Rac-specific inhibitor Bcr as a Tiam1-interacting protein that blocks Tiam1-induced Rac activation and actin remodeling. Overexpression and knockout experiments indicate that Bcr restricts the formation and growth of spines and dendrites. The complex between Tiam1 and Bcr may serve as an """"""""on-off switch"""""""" for precisely regulating Rac signaling in neurons, which is essential for the proper formation and remodeling of spines, synapses, and dendrites. To test this hypothesis, we propose the following specific aims: 1) to determine the role of Bcr in restricting synapse development and dendritic growth;2) to identify the mechanisms by which EphB and NMDA receptors regulate the Tiam1-Bcr complex, and determine the consequences on Rac activation and synapse development;and 3) to elucidate the role of the Tiam1-Bcr complex in regulating N-cadherin-mediated synaptic adhesion. To address these questions, we will use a multifaceted approach employing a combination of molecular, cellular, biochemical, and high-resolution imaging techniques. Results from the proposed studies will provide critical insight into the fundamental mechanisms that regulate Rac activation and Rac-dependent synaptic and dendritic development in neurons, and help to elucidate how disruptions in Rac GTPase signaling give rise to cognitive disorders such as mental retardation.

Public Health Relevance

We propose to investigate the mechanisms that regulate how connections in the brain (synapses) form during development and how they remodeling during processes like learning and memory. We are studying a particular signaling pathway that causes mental retardation when mutated in humans. Results from our studies should provide new insight into the fundamental mechanisms of brain development and memory formation, and should enhance our understanding of how disruptions in these processes give rise to brain disorders such as mental retardation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062829-05
Application #
8488493
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$317,549
Indirect Cost
$110,677
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Duman, Joseph G; Tu, Yen-Kuei; Tolias, Kimberley F (2016) Emerging Roles of BAI Adhesion-GPCRs in Synapse Development and Plasticity. Neural Plast 2016:8301737
Cadwell, Cathryn R; Palasantza, Athanasia; Jiang, Xiaolong et al. (2016) Electrophysiological, transcriptomic and morphologic profiling of single neurons using Patch-seq. Nat Biotechnol 34:199-203
Duman, Joseph G; Mulherkar, Shalaka; Tu, Yen-Kuei et al. (2015) Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses. Neurosci Lett 601:4-10
Um, Kyongmi; Niu, Sanyong; Duman, Joseph G et al. (2014) Dynamic control of excitatory synapse development by a Rac1 GEF/GAP regulatory complex. Dev Cell 29:701-15
Mulherkar, Shalaka; Uddin, Mohammad Danish; Couvillon, Anthony D et al. (2014) The small GTPases RhoA and Rac1 regulate cerebellar development by controlling cell morphogenesis, migration and foliation. Dev Biol 394:39-53
Reyes, Steve B; Narayanan, Anjana S; Lee, Hye Shin et al. (2013) αvβ8 integrin interacts with RhoGDI1 to regulate Rac1 and Cdc42 activation and drive glioblastoma cell invasion. Mol Biol Cell 24:474-82
Schwechter, Brandon; Tolias, Kimberley F (2013) Cytoskeletal mechanisms for synaptic potentiation. Commun Integr Biol 6:e27343
Mulherkar, Shalaka; Liu, Feng; Chen, Qin et al. (2013) The small GTPase RhoA is required for proper locomotor circuit assembly. PLoS One 8:e67015
Duman, Joseph G; Tzeng, Christopher P; Tu, Yen-Kuei et al. (2013) The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites. J Neurosci 33:6964-78
Schwechter, Brandon; Rosenmund, Christian; Tolias, Kimberley F (2013) RasGRF2 Rac-GEF activity couples NMDA receptor calcium flux to enhanced synaptic transmission. Proc Natl Acad Sci U S A 110:14462-7

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