REGULATORY MECHANISMS OF RAC-DEPENDENT DENDRITIC DEVELOPMENT AND PLASTICITY ABSTRACT 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 pooriy understood. We previously identified the Rac-specific activator Tiami as a critical regulator of dendrite, spine, and synapse development. We demonstrated that Tiami 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 Tiami-interacting protein that blocks Tiami-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 Tiami 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 Tiami-Bcr complex, and determine the consequences on Rac activation and synapse development;and 3) to elucidate the role of the Tiami-Bcr complex in regulating N-cadherinmediated 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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Center Core Grants (P30)
Project #
5P30HD024064-25
Application #
8508990
Study Section
Special Emphasis Panel (ZHD1-MRG-C)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
25
Fiscal Year
2013
Total Cost
$68,585
Indirect Cost
$23,903
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Itami, Chiaki; Huang, Jui-Yen; Yamasaki, Miwako et al. (2016) Developmental Switch in Spike Timing-Dependent Plasticity and Cannabinoid-Dependent Reorganization of the Thalamocortical Projection in the Barrel Cortex. J Neurosci 36:7039-54
Herrera, José A; Ward, Christopher S; Wehrens, Xander H T et al. (2016) Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis. Hum Mol Genet :
Machol, Keren; Jain, Mahim; Almannai, Mohammed et al. (2016) Corner fracture type spondylometaphyseal dysplasia: Overlap with type II collagenopathies. Am J Med Genet A :
Grafe, Ingo; Alexander, Stefanie; Yang, Tao et al. (2016) Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta. J Bone Miner Res 31:1030-40
Ure, Kerstin; Lu, Hui; Wang, Wei et al. (2016) Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. Elife 5:
Radtke-Schuller, Susanne; Schuller, Gerd; Angenstein, Frank et al. (2016) Brain atlas of the Mongolian gerbil (Meriones unguiculatus) in CT/MRI-aided stereotaxic coordinates. Brain Struct Funct 221 Suppl 1:1-272
Fountain, Michael D; Aten, Emmelien; Cho, Megan T et al. (2016) The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families. Genet Med :
Patil, Vinit V; Guzman, Miguel; Carter, Angela N et al. (2016) Activation of extracellular regulated kinase and mechanistic target of rapamycin pathway in focal cortical dysplasia. Neuropathology 36:146-56
White, Janson; Beck, Christine R; Harel, Tamar et al. (2016) POGZ truncating alleles cause syndromic intellectual disability. Genome Med 8:3
Rajagopal, Abbhirami; Homan, Erica P; Joeng, Kyu Sang et al. (2016) Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice. Mol Genet Metab 117:378-82

Showing the most recent 10 out of 667 publications