Heterotrimeric G proteins of the G q/11 family transduce signals from a variety of neurotransmitter and hormone receptors and have therefore been implicated in various functions of the nervous system. Using the Cre/loxP system, we generated mice which lack the genes coding for the ␣ subunits of the two main members of the G q/11 family, gnaq and gna11, selectively in neuronal and glial precursor cells. Mice with defective gnaq and gna11 genes were morphologically normal, but they died shortly after birth. Mice carrying a single gna11 allele survived the early postnatal period but died within 3 to 6 weeks as anorectic dwarfs. In these mice, postnatal proliferation of pituitary somatotroph cells was strongly impaired, and plasma growth hormone (GH) levels were reduced to 15%. Hypothalamic levels of GH-releasing hormone (GHRH), an important stimulator of somatotroph proliferation, were strongly decreased, and exogenous administration of GHRH restored normal proliferation. The hypothalamic effects of ghrelin, a regulator of GHRH production and food intake, were reduced in these mice, suggesting that an impairment of ghrelin receptor signaling might contribute to GHRH deficiency and abnormal eating behavior. Taken together, our findings show that G q/11 signaling is required for normal hypothalamic function and that impairment of this signaling pathway causes somatotroph hypoplasia, dwarfism, and anorexia.The G q/11 family of heterotrimeric G proteins mediates the cellular effects of numerous neurotransmitter receptors, e.g., the metabotropic glutamate receptor subtypes 1 and 5, the M 1 muscarinic-acetylcholine receptor, the 5-HT 2 serotonin receptors, or the ␣ 1 adrenergic receptor. G q/11 -coupled receptors are also involved in the signal transduction of several hypothalamic peptide hormone receptors, such as the receptors for thyrotropin-releasing hormone (39), gonadotropin-releasing hormone (13), and prolactin-releasing hormones (3). There is an increasing amount of evidence that the release of hypothalamic hormones themselves is also controlled by G q/11 -coupled receptors. Kisspeptins, for example, have been suggested to control the release of gonadotropin-releasing hormone via the G q/11 -coupled receptor GPR54 (14,20), and the gastrointestinal peptide hormone ghrelin regulates the production of growth hormone-releasing hormone (GHRH) via the hypothalamic growth hormone secretagogue receptor (GHS-R) (12,22). G q/11 family G proteins mediate the activation of ␤ isoforms of phospholipase C, resulting in the activation of protein kinase C and intracellular calcium mobilization (2). The G q/11 family consists of four members, two of which, G q and G 11 , are expressed almost ubiquitously in the central nervous system (26). Genetic inactivation of the gnaq gene, which codes for the ␣ subunit of G q (G␣ q ), leads to a defect in primary hemostasis (16) and cerebellar ataxia (15). In contrast, mice homozygous for a null allele of the gene coding for G␣ 11 , gna11, did not show any phenotypic abnormalities (17). These...

G protein-coupled receptors play an important role in the regulation of lymphocyte functions such as migration, adhesion, proliferation, and differentiation. Although the role of Gi family G proteins has been intensively studied, no in vivo data exist with respect to G12/G13 family G proteins. We show in this study that mice that lack the G protein α-subunits Gα12 and Gα13 selectively in B cells show significantly reduced numbers of splenic marginal zone B (MZB) cells, resulting in a delay of Ab production in response to thymus-independent Ags. Basal and chemokine-induced adhesion to ICAM-1 and VCAM-1, two adhesion molecules critically involved in MZB localization, is normal in mutant B cells, and the same is true for chemokine-induced migration. However, migration in response to serum and sphingosine 1-phosphate is strongly increased in mutant MZB cells, but not in mutant follicular B cells. Live-cell imaging studies revealed that Gα12/Gα13-deficient MZB cells assumed more frequently an ameboid form than wild-type cells, and pseudopod formation was enhanced. In addition to their regulatory role in serum- and sphingosine 1-phosphate-induced migration, G12/G13 family G proteins seem to be involved in peripheral MZB cell maturation, because also splenic MZB cell precursors are reduced in mutant mice, although less prominently than mature MZB cells. These data suggest that G12/G13 family G proteins contribute to the formation of the mature MZB cell compartment both by controlling MZB cell migration and by regulating MZB cell precursor maturation.

Integrin-mediated adhesion is a crucial step in lymphocyte extravasation and homing. We show here that not only the chemokines CXCL12 and CXCL13 but also the lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) enhance adhesion of murine follicular and marginal zone B cells to ICAM-1 in vitro. This process involves clustering of integrin LFA-1 and is blocked by pertussis toxin, suggesting that G i family G-proteins are involved. In addition, lysophospholipid-induced adhesion on ICAM-1 depends on Rho and Rhokinase, indicative of an involvement of G 12 /G 13 , possibly also G q /G 11 family G-proteins. We used G 12 /G 13 -or G q /G 11 -deficient B cells to study the role of these G-protein families in lysophospholipid-induced adhesion and found that the pro-adhesive effects of LPA and S1P are completely abrogated in G 12 / G 13 -deficient marginal zone B cells, reduced in G 12 /G 13 -deficient follicular B cells, and normal in G q /G 11 -deficient B cells. We also show that loss of lysophospholipid-induced adhesion results in disinhibition of migration in response to the follicular chemokine CXCL13, which might contribute to the abnormal localization of splenic B cell populations observed in B cell-specific G 12 /G 13 -deficient mice in vivo. Taken together, this study shows that lysophospholipids regulate integrin-mediated adhesion of splenic B cells to ICAM-1 through G i and G 12 /G 13 family G-proteins but not through G q /G 11 .Integrins are adhesion receptors that connect cells to extracellular matrix or to counter-receptors on other cells. Integrinmediated adhesion is critically involved in a variety of processes such as tissue morphogenesis, wound healing, blood clotting, and leukocyte trafficking.In leukocytes, chemokines and their G-protein coupled receptors (GPCRs) 2 play an important role in the regulation of integrin activity. While a wealth of studies addressed the role of chemokine receptors in lymphocyte homing to lymph nodes and PeyerЈs patches (1, 2), not much is known about the regulation of B lymphocyte adhesion in the spleen. The spleen contains two subpopulations of mature B cells, follicular B cells and marginal zone B (MZ B) cells, the latter residing at the interface between red and white pulp, the marginal zone. Due to this localization at a site of early antigen contact and due to their high proliferative capacity, MZ B cells play an important role in the rapid defense against blood-borne bacterial antigens (3, 4). Both entry of follicular B cells into the white pulp (5) and MZ B cell localization within the marginal zone (6) depend on the interaction between lymphocyte integrins LFA (leukocyte function antigen)-1 and ␣ 4 ␤ 1 and their respective ligands on stromal cells, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), respectively. A role for GPCRs in the regulation of this interaction was suggested based on pharmacological or genetic inactivation of different G-protein families in mice. For example, treatment with p...