Pharmacogenetic Analysis Reveals a Post-Developmental Role for Rac GTPases in<i>Caenorhabditis elegans</i>GABAergic Neurotransmission

Genetics - Tập 183 Số 4 - Trang 1357-1372 - 2009
Cody J. Locke1, Bwarenaba B Kautu2, Kalen Berry2, S. Kyle Lee2, Kim A. Caldwell2,3, Guy A. Caldwell2,3
1Departments of Neurobiology and Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama, Birmingham, Alabama 35294, USA.
2Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487, and.
3Departments of Neurobiology and Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama , Birmingham, Alabama 35294

Tóm tắt

AbstractThe nerve-cell cytoskeleton is essential for the regulation of intrinsic neuronal activity. For example, neuronal migration defects are associated with microtubule regulators, such as LIS1 and dynein, as well as with actin regulators, including Rac GTPases and integrins, and have been thought to underlie epileptic seizures in patients with cortical malformations. However, it is plausible that post-developmental functions of specific cytoskeletal regulators contribute to the more transient nature of aberrant neuronal activity and could be masked by developmental anomalies. Accordingly, our previous results have illuminated functional roles, distinct from developmental contributions, for Caenorhabditis elegans orthologs of LIS1 and dynein in GABAergic synaptic vesicle transport. Here, we report that C. elegans with function-altering mutations in canonical Rac GTPase-signaling-pathway members demonstrated a robust behavioral response to a GABAA receptor antagonist, pentylenetetrazole. Rac mutants also exhibited hypersensitivity to an acetylcholinesterase inhibitor, aldicarb, uncovering deficiencies in inhibitory neurotransmission. RNA interference targeting Rac hypomorphs revealed synergistic interactions between the dynein motor complex and some, but not all, members of Rac-signaling pathways. These genetic interactions are consistent with putative Rac-dependent regulation of actin and microtubule networks and suggest that some cytoskeletal regulators cooperate to uniquely govern neuronal synchrony through dynein-mediated GABAergic vesicle transport in C. elegans.

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Tài liệu tham khảo

2006, Neurobiol. Dis., 22, 374, 10.1016/j.nbd.2005.12.012

2007, Nat. Cell Biol., 9, 1381, 10.1038/ncb1657

2005, Neuroscience, 131, 759, 10.1016/j.neuroscience.2004.11.031

1997, Neuron, 19, 51, 10.1016/S0896-6273(00)80347-5

1974, Genetics, 77, 95, 10.1093/genetics/77.1.95

2006, J. Neurosci., 26, 6813, 10.1523/JNEUROSCI.5320-05.2006

2007, Dev. Biol., 305, 397, 10.1016/j.ydbio.2007.02.024

2002, Hum. Mutat., 19, 4, 10.1002/humu.10028

2006, J. Neurosci., 26, 223, 10.1523/JNEUROSCI.4110-05.2006

2005, Nat. Neurosci., 8, 1059, 10.1038/nn1499

2002, Nat. Genet., 31, 184, 10.1038/ng885

2004, Development, 131, 2073, 10.1242/dev.01063

2001, Dev. Genes Evol., 211, 434, 10.1007/s004270100176

2008, Dev. Neurosci., 30, 47, 10.1159/000109851

1998, J. Neurosci., 18, 8505, 10.1523/JNEUROSCI.18-20-08505.1998

2000, Proc. Natl. Acad. Sci. USA, 97, 2674, 10.1073/pnas.97.6.2674

2000, Neuron, 28, 115, 10.1016/S0896-6273(00)00090-8

2002, Neuron, 33, 789, 10.1016/S0896-6273(02)00601-3

1991, Genetics, 129, 79, 10.1093/genetics/129.1.79

1999, J. Neurochem., 72, 318, 10.1111/jnc.1999.72.1.318

2007, Nat. Neurosci., 10, 411, 10.1038/nn1860

2003, Neuron, 37, 53, 10.1016/S0896-6273(02)01149-2

2005, Neuron, 48, 91, 10.1016/j.neuron.2005.08.036

2005, Mech. Dev., 122, 97, 10.1016/j.mod.2004.08.005

2001, J. Pharmacol. Exp. Ther., 298, 986

2006, J. Neurosci., 26, 11208, 10.1523/JNEUROSCI.3526-06.2006

2007, PLoS Biol., 5, e237, 10.1371/journal.pbio.0050237

2005, J. Biol. Chem., 280, 2065, 10.1074/jbc.M408470200

1994, Nature, 372, 780, 10.1038/372780a0

2003, Nature, 421, 231, 10.1038/nature01278

2003, Genetics, 164, 153, 10.1093/genetics/164.1.153

2007, Cell, 128, 45, 10.1016/j.cell.2006.12.017

2003, J. Neurosci., 23, 8673, 10.1523/JNEUROSCI.23-25-08673.2003

2006, Nat. Neurosci., 9, 50, 10.1038/nn1619

2005, Nature, 434, 93, 10.1038/nature03263

2002, Dev. Biol., 241, 339, 10.1006/dbio.2001.0513

1999, Development, 126, 4489, 10.1242/dev.126.20.4489

2004, J. Neurosci., 24, 3907, 10.1523/JNEUROSCI.5039-03.2004

2007, Nature, 445, 168, 10.1038/nature05453

2006, Brain Res., 1120, 23, 10.1016/j.brainres.2006.08.067

2008, J. Vis. Exp., 18, 837

2009

1997, Hum. Mol. Genet., 6, 157, 10.1093/hmg/6.2.157

2005, Biochem. Biophys. Res. Commun., 331, 153, 10.1016/j.bbrc.2005.03.128

2006, Development, 133, 4549, 10.1242/dev.02648

2001, Development, 128, 4475, 10.1242/dev.128.22.4475

2006, Neuron, 51, 303, 10.1016/j.neuron.2006.06.025

1993, Nature, 364, 334, 10.1038/364334a0

2006, Genes. Dev., 20, 65, 10.1101/gad.359706

2007, Anal. Biochem., 368, 178, 10.1016/j.ab.2007.05.022

1996, Proc. Natl. Acad. Sci. USA, 93, 12593, 10.1073/pnas.93.22.12593

1995, Genetics, 140, 527, 10.1093/genetics/140.2.527

1997, J. Neurosci., 17, 8061, 10.1523/JNEUROSCI.17-21-08061.1997

1998, J. Neurosci., 18, 70, 10.1523/JNEUROSCI.18-01-00070.1998

2004, J. Neurosci., 24, 9005, 10.1523/JNEUROSCI.2943-04.2004

1994, Cell, 79, 23, 10.1016/0092-8674(94)90397-2

1998, Brain Res. Mol. Brain Res., 55, 265, 10.1016/S0169-328X(98)00007-2

2002, Curr. Biol., 12, 622, 10.1016/S0960-9822(02)00764-9

2000, J. Neurosci., 20, 4337, 10.1523/JNEUROSCI.20-11-04337.2000

2005, Mol. Biol. Cell, 16, 2759, 10.1091/mbc.e05-01-0069

1999, Nat. Neurosci., 2, 791, 10.1038/12160

2000, Genetics, 156, 1069, 10.1093/genetics/156.3.1069

2005, Mol. Biol. Cell, 16, 483, 10.1091/mbc.e04-07-0553

2004, Trends Neurosci., 27, 407, 10.1016/j.tins.2004.05.005

2006, Genetics, 172, 893, 10.1534/genetics.105.046359

1998, Cell, 92, 785, 10.1016/S0092-8674(00)81406-3

2005, Genes Dev., 19, 2016, 10.1101/gad.1319905

2003, Development, 130, 693, 10.1242/dev.00300

1975, J. Comp. Neurol., 163, 215, 10.1002/cne.901630207

2006, Genome Biol., 7, R69, 10.1186/gb-2006-7-8-r69

2008, Neuron, 58, 346, 10.1016/j.neuron.2008.02.019

2001, J. Neurosci., 21, 983, 10.1523/JNEUROSCI.21-03-00983.2001

2007, Genes Dev., 21, 2731, 10.1101/gad.1592007

2004, Hum. Mol. Genet., 13, 2043, 10.1093/hmg/ddh209

2002, Dev. Biol., 250, 145, 10.1006/dbio.2002.0785

2008, PLoS ONE, 3, e2056, 10.1371/journal.pone.0002056

2006, Genetics, 174, 1917, 10.1534/genetics.106.063115

1997, Cell, 90, 883, 10.1016/S0092-8674(00)80353-0