G␣15 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. G␣15 is primarily expressed in hematopoietic cells in fetal and adult mice. We disrupted the G␣15 gene by homologous recombination in embryonic stem cells to identify its biological functions. Surprisingly, hematopoiesis was normal in G␣15 ؊/؊ macrophages. Despite discrete signaling defects, compensation by coexpressed Gq and/or Gi class ␣ subunits may suppress abnormalities in G␣15-deficient mice.Heterotrimeric G proteins transduce signals from ligandactivated seven-transmembrane domain receptors to effector proteins that regulate the release of intracellular second messengers, such as Ca 2ϩ and cyclic AMP. A diverse family of G-protein-coupled receptors bind numerous hormones and neurotransmitters, peptides, small proteins, and lipid molecules. The biological functions mediated by G proteins are equally diverse, including behavioral and sensory functions, appetite control, arousal, metabolism, development, inflammation, and chemotaxis.Heterotrimeric G proteins are composed of ␣ and ␥ subunits that can independently regulate effector proteins. Mammals express 16 distinct G␣ subunit genes that are grouped in four classes, Gq, Gi, Gs, and G12, according to sequence similarity, effector regulation, and responsiveness to RGS (regulators of G-protein signaling) proteins, a recently identified family of GTPase-activating proteins (GAPs) for G␣ subunits (30). The Gq class ␣ subunits activate all isoforms of phospholipase C (PLC), which hydrolyze the membrane lipid phosphatidylinositol-4,5-bisphosphate to produce inositol trisphosphate and diacylglycerol. PLC2 and PLC3 are also activated by G␥ subunits, primarily released from Gi class G proteins (31), which is the basis for pertussis toxin inhibition of PLC activity and Ca 2ϩ signaling evoked by Gi-coupled receptors (2, 20). Inositol trisphosphate produced by the activity of PLC evokes calcium release from intracellular stores, and diacyl-