Kalirin is a large, multidomain Rho GDP/GTP exchange factor (GEF) of the Dbl family found almost exclusively in the nervous system. Based on genetic studies in invertebrates and analysis of genes involved in X-linked mental retardation, Kalirin is expected to play a role in axonal pathfinding and synapse formation. Our studies in rat hippocampal, cortical and sympathetic neurons showed that Kalirin plays a role in axon initiation and outgrowth, dendritic growth, and spine formation and maintenance. Kalirin has two GEF domains with specificity for different Rho family GTPases and a potential kinase domain. In addition to these catalytic domains, it has interactor domains for a variety of proteins. Kalirin expression in the nucleus accumbens and striatum is stimulated by chronic administration of cocaine, with no change in cortical Kalirin levels; Kalirin is also increased following electroconvulsive shock stimulation. The exploratory studies proposed are based on our observations that antisense-mediated elimination of Kalirin expression in organotypic slices and dissociated hippocampal neurons leads first to a reduction in linear spine density followed by simplification of the dendritic tree.
Aim 1 is to generate mutant mice that will facilitate studies of neuronal development and plasticity in multiple systems. In order to avoid embryonic or early postnatal lethality, and to allow generation of tissue-specific and developmentally regulated elimination of expression, two mouse lines will be created as floxed alleles. Both will be provided to all qualified investigators without restrictions. One allele will produce the Kalirin-7 null. Kalirin-7 is the most prevalent isoform in the adult brain, with a single Rho GEF domain, terminating with a unique PDZ binding motif. Kalirin-7 appears late in development and is localized to dendritic spines. The second allele will produce the total Kalidn knockout. Both will be bred with available tissue-specific and drug-inducible Cre recombinase mice.
Aim 2 will examine the biochemical, histological, and developmental consequences of tissue-specific Kalirin conditional knockouts.
| Miller, Megan B; Yan, Yan; Eipper, Betty A et al. (2013) Neuronal Rho GEFs in synaptic physiology and behavior. Neuroscientist 19:255-73 |
| Kiraly, Drew D; Nemirovsky, Natali E; LaRese, Taylor P et al. (2013) Constitutive knockout of kalirin-7 leads to increased rates of cocaine self-administration. Mol Pharmacol 84:582-90 |
| Eipper-Mains, Jodi E; Eipper, Betty A; Mains, Richard E (2012) Global Approaches to the Role of miRNAs in Drug-Induced Changes in Gene Expression. Front Genet 3:109 |
| Ma, Xin-Ming; Huang, Jian-Ping; Xin, Xiaonan et al. (2012) A role for kalirin in the response of rat medium spiny neurons to cocaine. Mol Pharmacol 82:738-45 |
| Mazzone, Christopher M; Larese, Taylor P; Kiraly, Drew D et al. (2012) Analysis of kalirin-7 knockout mice reveals different effects in female mice. Mol Pharmacol 82:1241-9 |
| Mandela, Prashant; Yankova, Maya; Conti, Lisa H et al. (2012) Kalrn plays key roles within and outside of the nervous system. BMC Neurosci 13:136 |
| Kiraly, Drew D; Lemtiri-Chlieh, Fouad; Levine, Eric S et al. (2011) Kalirin binds the NR2B subunit of the NMDA receptor, altering its synaptic localization and function. J Neurosci 31:12554-65 |
| Kiraly, Drew D; Stone, Kathy L; Colangelo, Chris M et al. (2011) Identification of kalirin-7 as a potential post-synaptic density signaling hub. J Proteome Res 10:2828-41 |
| Lemtiri-Chlieh, Fouad; Zhao, Liangfang; Kiraly, Drew D et al. (2011) Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity. BMC Neurosci 12:126 |
| Kiraly, Drew D; Ma, Xin-Ming; Mazzone, Christopher M et al. (2010) Behavioral and morphological responses to cocaine require kalirin7. Biol Psychiatry 68:249-55 |
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