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Molecular and Cellular Biology, May 2007, p. 3470-3480, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.00659-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Targeting of the ETS Factor Gabp{alpha} Disrupts Neuromuscular Junction Synaptic Function{triangledown} ,§

Debra A. O'Leary,1,{dagger} Peter G. Noakes,2 Nick A. Lavidis,2 Ismail Kola,1,{ddagger} Paul J. Hertzog,1* and Sika Ristevski1

Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia,1 School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia2

Received 15 April 2006/ Returned for modification 10 June 2006/ Accepted 30 October 2006

The GA-binding protein (GABP) transcription factor has been shown in vitro to regulate the expression of the neuromuscular proteins utrophin, acetylcholine esterase, and acetylcholine receptor subunits {delta} and {varepsilon} through the N-box promoter motif (5'-CCGGAA-3'), but its in vivo function remains unknown. A single point mutation within the N-box of the gene encoding the acetylcholine receptor {varepsilon} subunit has been identified in several patients suffering from postsynaptic congenital myasthenic syndrome, implicating the GA-binding protein in neuromuscular function and disease. Since conventional gene targeting results in an embryonic-lethal phenotype, we used conditional targeting to investigate the role of GABP{alpha} in neuromuscular junction and skeletal muscle development. The diaphragm and soleus muscles from mutant mice display alterations in morphology and distribution of acetylcholine receptor clusters at the neuromuscular junction and neurotransmission properties consistent with reduced receptor function. Furthermore, we confirmed decreased expression of the acetylcholine receptor {varepsilon} subunit and increased expression of the {gamma} subunit in skeletal muscle tissues. Therefore, the GABP transcription factor aids in the structural formation and function of neuromuscular junctions by regulating the expression of postsynaptic genes.

* Corresponding author. Mailing address: Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Phone: 61 3 9594 7236. Fax: 61 3 9594 7211. E-mail: Paul.Hertzog{at}med.monash.edu.au

{triangledown} Published ahead of print on 26 February 2007.

§ Supplemental material for this article may be found at http://mcb.asm.org.

{dagger} Present address: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121.

{ddagger} Present address: Merck Research Laboratories, Merck & Co., 126 East Lincoln Avenue, Rahway, NJ 07065.

Molecular and Cellular Biology, May 2007, p. 3470-3480, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.00659-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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