Dendritic spine remodeling is a key component of synaptic development and plasticity, and it is profoundly affected in neurodevelopmental and neurodegenerative disorders. Spine morphological changes require precise coordination of adhesion, cytoskeletal reorganization, and functional modulation. The crucial role of adhesion in regulating spine morphology has only begun to be elucidated. N-cadherin, a major synaptic adhesion molecule, influences spine structure through the actions of alpha-N-catenin, Rho GTPases, and actin rearrangement, but the specifics of this signaling mechanism remain unclear. Additionally, adhesion molecules called nectins have been implicated in synapse formation in a potentially cooperative association with N-cadherins;however, the exact relationship between these pathways is unknown. AF-6, a PDZ protein component prevalent in adhesion junctions and in central synapses, has been shown to interact with both alpha-N-catenins and nectins. Preliminary data from our laboratory have shown that AF-6 interacts with the Rac GEF kalirin-7, a key regulator of dendritic spine morphology, placing AF-6 in an ideal position to integrate adhesion and dendritic spine structural plasticity.
The aim of this proposed work is to determine the relative roles of the N-cadherin adhesion complex and the nectin adhesion complex in regulating the activity of AF-6 and its subsequent remodeling of dendritic spine structure. First, we will characterize the interactions between AF-6 and N-cadherin or nectins by coimmunoprecipitation from synaptosomes. We will also determine the structural basis for the AF-6/N-cadherin complex interaction by affinity binding assays of mutant AF-6 proteins with synaptosome extracts, and compare these important structural domains to the known binding domain of AF-6 with nectins. We will then measure AF-6 recruitment to spines by N-cadherin complexes or by nectins upon their activation, to determine the relative importance of each pathway in regulating AF-6 function. Finally, we will compare the relative importance of alpha-N-catenin, nectins, and AF-6 in N-cadherin-mediated spine remodeling by using dominant-negative constructs and then enhancing or blocking N-cadherin signaling. The results from these aims will allow a better understanding of the regulation adhesion-mediated remodeling of dendritic spine structure by AF-6, and will provide insight into the mechanisms of structural plasticity in health and in disease states.

Public Health Relevance

The goal of this project is to understand how connections between nerve cells in the brain are established. Many brain disorders are caused by abnormal connection strength and numbers, and understanding how these connections are formed will provide potential targets for drugs that might be used to treat these devastating disorders

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH085362-02
Application #
7693827
Study Section
Special Emphasis Panel (ZRG1-F03A-F (20))
Program Officer
Desmond, Nancy L
Project Start
2008-09-22
Project End
2011-09-21
Budget Start
2009-09-22
Budget End
2010-09-21
Support Year
2
Fiscal Year
2009
Total Cost
$28,097
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Jones, Kelly A; Eng, Andrew G; Raval, Pooja et al. (2014) Scaffold protein X11? interacts with kalirin-7 in dendrites and recruits it to Golgi outposts. J Biol Chem 289:35517-29
Cahill, Michael E; Remmers, Christine; Jones, Kelly A et al. (2013) Neuregulin1 signaling promotes dendritic spine growth through kalirin. J Neurochem 126:625-35
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Srivastava, Deepak P; Copits, Bryan A; Xie, Zhong et al. (2012) Afadin is required for maintenance of dendritic structure and excitatory tone. J Biol Chem 287:35964-74
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