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Molecular and Cellular Biology, September 2006, p. 6870-6879, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.00314-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pleiotropic Phenotype of a Genomic Knock-In of an RGS-Insensitive G184S Gnai2 Allele

Xinyan Huang,1 Ying Fu,1 Raelene A. Charbeneau,1 Thomas L. Saunders,2 Douglas K. Taylor,3 Kurt D. Hankenson,3,4 Mark W. Russell,5 Louis G. D'Alecy,6,7 and Richard R. Neubig1*

Department of Pharmacology,1 Department of Internal Medicine, Transgenic Animal Model Core,2 Unit for Laboratory Animal Medicine,3 Departments of Biomedical Engineering, Cell and Developmental Biology, and Orthopaedic Surgery,4 Department of Pediatrics and Communicable Diseases,5 Departments of Molecular and Integrative Physiology and Vascular Surgery, University of Michigan, Ann Arbor, Michigan,6 Department of Surgery, William Beaumont Hospital, Royal Oak, Michigan7

Received 20 February 2006/ Returned for modification 12 June 2006/ Accepted 23 June 2006

Signal transduction via guanine nucleotide binding proteins (G proteins) is involved in cardiovascular, neural, endocrine, and immune cell function. Regulators of G protein signaling (RGS proteins) speed the turn-off of G protein signals and inhibit signal transduction, but the in vivo roles of RGS proteins remain poorly defined. To overcome the redundancy of RGS functions and reveal the total contribution of RGS regulation at the G{alpha}i2 subunit, we prepared a genomic knock-in of the RGS-insensitive G184S Gnai2 allele. The G{alpha}i2G184S knock-in mice show a dramatic and complex phenotype affecting multiple organ systems (heart, myeloid, skeletal, and central nervous system). Both homozygotes and heterozygotes demonstrate reduced viability and decreased body weight. Other phenotypes include shortened long bones, a markedly enlarged spleen, elevated neutrophil counts, an enlarged heart, and behavioral hyperactivity. Heterozygous G{alpha}i2+/G184S mice show some but not all of these abnormalities. Thus, loss of RGS actions at G{alpha}i2 produces a dramatic and pleiotropic phenotype which is more evident than the phenotype seen for individual RGS protein knockouts.

* Corresponding author. Mailing address: Department of Pharmacology, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109. Phone: (734) 763-3650. Fax: (734) 763-4450. E-mail: rneubig{at}umich.edu.

Molecular and Cellular Biology, September 2006, p. 6870-6879, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.00314-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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