Neural circuits do not develop properly in neurodevelopmental disorders and degrade prematurely in neurodegenerative disorders. We have shown that dendritic spine morphogenesis and later synapse and dendrite stability requires the Abl-related gene (Arg) nonreceptor tyrosine kinase, which acts downstream of integrin adhesion receptors to mediate changes in cytoskeletal structure. We seek to understand how integrins signal through Arg and its effectors to control the formation and maintenance of neural circuitry.
Our first aim i s to elucidate the roles for Arg in dendritic spine morphology, synapse stability, and dendrite maintenance. Dendrites and synapses develop normally through postnatal day 21 in the arg-/- mouse cortex and hippocampus, but dendritic spines do not mature properly, leading to synapse and dendrite loss and behavioral deficits by postnatal day 42. We will use electrophysiology and analyze three-dimensional reconstructions of synapses and dendrites in arg-/- mice to examine how the loss of Arg-signaling pathways compromises the formation, stability, and function of synapses and dendrites. We will also use a conditionally inactivatable arg allele and an inducible arg transgene to determine when Arg signaling is required for proper synapse development and to protect against synapse loss and dendritic degeneration.
Our second aim i s to understand how integrins activate Arg to regulate synapse and dendrite stability. Our work has shown that integrins act through Arg to mediate changes in cytoskeletal structure, but we do not understand how Arg is recruited to integrin heterodimers to achieve kinase activation in vivo. We will test the hypothesis, supported by preliminary data, that integrin 21 or 23 cytoplasmic tails bind directly to Arg to mediate kinase activation. Integrins containing 21 or 23 subunits regulate synapse formation and dendrite stability in vivo, but it is unclear which specific integrin heterodimers act through Arg to regulate synapse and dendrite maintenance. We will monitor Arg signaling pathways and analyze synapse and dendrite structure in integrin 21 and 23 mutant mice to determine which integrins act through Arg to control dendritic spine morphogenesis and synapse/dendrite stability.
Our third aim i s to determine how Arg signals through its effectors to regulate synapse and dendrite stability. Arg is required for proper dendritic spine morphogenesis in vivo, but we do not understand how Arg coordinates the cytoskeletal changes required for these processes. Our biochemical studies have identified several substrates (p190RhoGAP, cortactin, myosin IIB) through which Arg acts to promote changes in cytoskeletal structure. We will examine how integrin signaling through Arg affects the distribution of these Arg substrates in cultured cortical neurons. We will also test whether RNAi knockdown of the substrates affects dendritic spine structure and synapse and dendrite stability in established hippocampal neuronal cultures.

Public Health Relevance

Neural circuits do not develop properly in neurodevelopmental disorders, such as mental retardation, and degrade prematurely in neurodegenerative disorders, such as Alzheimer's Disease. Defects in synapse function and/or reductions in synapse number lead to the loss of dendrite segments and degeneration of neural circuits. We will study a biochemical pathway that regulates synapse morphogenesis and function and protects against degeneration of neural circuits in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039475-13
Application #
8272555
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
2000-02-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2012
Total Cost
$354,791
Indirect Cost
$140,416
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Gifford, Stacey M; Liu, Weizhi; Mader, Christopher C et al. (2014) Two amino acid residues confer different binding affinities of Abelson family kinase SRC homology 2 domains for phosphorylated cortactin. J Biol Chem 289:19704-13
Cooper, Margaret A; Koleske, Anthony J (2014) Ablation of ErbB4 from excitatory neurons leads to reduced dendritic spine density in mouse prefrontal cortex. J Comp Neurol 522:3351-62
Lin, Yu-Chih; Yeckel, Mark F; Koleske, Anthony J (2013) Abl2/Arg controls dendritic spine and dendrite arbor stability via distinct cytoskeletal control pathways. J Neurosci 33:1846-57
Bryce, Nicole S; Reynolds, Albert B; Koleske, Anthony J et al. (2013) WAVE2 regulates epithelial morphology and cadherin isoform switching through regulation of Twist and Abl. PLoS One 8:e64533
Kerrisk, Meghan E; Koleske, Anthony J (2013) Arg kinase signaling in dendrite and synapse stabilization pathways: memory, cocaine sensitivity, and stress. Int J Biochem Cell Biol 45:2496-500
Gourley, Shannon L; Swanson, Andrew M; Koleske, Anthony J (2013) Corticosteroid-induced neural remodeling predicts behavioral vulnerability and resilience. J Neurosci 33:3107-12
Kerrisk, Meghan E; Greer, Charles A; Koleske, Anthony J (2013) Integrin *3 is required for late postnatal stability of dendrite arbors, dendritic spines and synapses, and mouse behavior. J Neurosci 33:6742-52
Koleske, Anthony J (2013) Molecular mechanisms of dendrite stability. Nat Rev Neurosci 14:536-50
Couch, Brian A; Kerrisk, Meghan E; Kaufman, Adam C et al. (2013) Delayed amyloid plaque deposition and behavioral deficits in outcrossed A*PP/PS1 mice. J Comp Neurol 521:1395-408
Warren, M Sloan; Bradley, William D; Gourley, Shannon L et al. (2012) Integrin *1 signals through Arg to regulate postnatal dendritic arborization, synapse density, and behavior. J Neurosci 32:2824-34

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