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Molecular and Cellular Biology, February 2000, p. 797-804, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Normal Hematopoiesis and Inflammatory Responses Despite Discrete Signaling Defects in G15 Knockout Mice

I. Davignon,^1, M. D. Catalina,^2, D. Smith,¹ J. Montgomery,³ J. Swantek,¹ J. Croy,⁴ M. Siegelman,² and T. M. Wilkie^1,*

Pharmacology Department, UT Southwestern, Dallas TX 75235-9041¹; Pathology Department, UT Southwestern, Dallas TX 75235-9072²; Biology Department, Center for Parasitology, UT Arlington, Arlington, TX 76019³; and Physiology Department, UT Southwestern, Dallas TX 75235-9040⁴

Received 1 November 1999/Accepted 4 November 1999

G15 activates phospholipase C in response to the greatest variety of agonist-stimulated heptahelical receptors among the four Gq class G-protein  subunits expressed in mammals. G15 is primarily expressed in hematopoietic cells in fetal and adult mice. We disrupted the G15 gene by homologous recombination in embryonic stem cells to identify its biological functions. Surprisingly, hematopoiesis was normal in G15^/ mice, G15^/ Gq^/ double-knockout mice (which express only G11 in most hematopoietic cells), and G11^/ mice, suggesting functional redundancy in Gq class signaling. Inflammatory challenges, including thioglycolate-induced peritonitis and infection with Trichinella spiralis, stimulated similar responses in G15^/ adults and wild-type siblings. Agonist-stimulated Ca²⁺ release from intracellular stores was assayed to identify signaling defects in primary cultures of thioglycolate-elicited macrophages isolated from G15^/ mice. C5a-stimulated phosphoinositide accumulation and Ca²⁺ release was significantly reduced in G15^/ macrophages. Ca²⁺ signaling was abolished only in mutant cells pretreated with pertussis toxin, suggesting that the C5a receptor couples to both G15 and Gi in vivo. Signaling evoked by other receptors coupled by Gq class  subunits appeared normal in G15^/ macrophages. Despite discrete signaling defects, compensation by coexpressed Gq and/or Gi class  subunits may suppress abnormalities in G15-deficient mice.

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^* Corresponding author. Mailing address: Pharmacology Department, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9041. Phone: (214) 648-8581. Fax: (214) 648-8626. E-mail: thomas.wilkie{at}emailswmed.edu.

Present address: Department of Molecular Genetics, UT Southwestern, Dallas TX 75235-9050.

Present address: Division of Pediatric Immunology, University of Massachusetts Medical Center, Worcester, MA 01606.

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Molecular and Cellular Biology, February 2000, p. 797-804, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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