Loss of G_q/11 Family G Proteins in the Nervous System Causes Pituitary Somatotroph Hypoplasia and Dwarfism in Mice

Abstract

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...

GH in the dwarf dopaminergic D2 receptor knockout mouse: somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin

“…Its signal transduction involves activation of phospholipase C (via G protein), generation of inositol phosphate and diacyl glycerol, and increased intracellular Ca 2C . It has been described that ghrelin-induced GH release is inhibited in mice with dwarfism due to the loss of G q/11 family G proteins in the central nervous system (Wettschureck et al 2005). However, we found no significant differences in ghrelininduced GH release between genotypes, other than the proportional decrease due to diminished number of somatotropes.…”

Neuronal M 3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

“…As a result, the NesCre transgene used in the present study is not expressed in the anterior pituitary (23,32). It is therefore unlikely that the defect leading to the hypoplasia of the anterior pituitary in the Br-M3-KO mice resides in the pituitary itself.…”

“…As a result, the NesCre transgene is not expressed in the anterior pituitary (23,32). It seemed therefore reasonable to assume that the defect leading to the hypoplasia of the anterior pituitary in Br-M3-KO-mice does not reside in the pituitary itself but involves other brain regions that stimulate the growth of the anterior pituitary.…”

Ghrelin Gene Products and the Regulation of Food Intake and Gut Motility

“…GHS-R1b is derived from the only first exon, encodes only five of the seven predicted TMs, and is thus a COOH-terminally truncated form of GHS-R1a and is pharmacologically inactive (Howard et al, 1996;Kojima and Kangawa, 2005). Acyl ghrelin acts on GHS-R1a, which belongs to family A, and, in turn, signals via a G q/11 ␣-subunit that results in the release of inositol trisphosphate and Ca 2ϩ (Howard et al, 1996;Guan et al, 1997;Wettschureck et al, 2005). GHS-R1b interacts with GHS-R1a and neurotensin receptor 1 to form heterodimer (Takahashi et al, 2006b).…”