Loss of Gq/11 family G proteins in the nervous system causes pituitary somatotroph hypoplasia and dwarfism in mice.
Heterotrimeric G proteins of the Gq/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 alpha subunits of the two main members of the Gq/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 Gq/11 signaling is required for normal hypothalamic function and that impairment of this signaling pathway causes somatotroph hypoplasia, dwarfism, and anorexia.
Wettschureck
N
N
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Nina.Wettschureck@urz.uni-heidelberg.de
Moers
A
A
Wallenwein
B
B
Parlow
A F
AF
Maser-Gluth
C
C
Offermanns
S
S
D000483:Alleles; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004393:Dwarfism, Pituitary / Q000209:etiology* / Q000378:metabolism; D004435:Eating / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D054439:Ghrelin; D013006:Growth Hormone / Q000032:analysis / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007031:Hypothalamus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009929:Organ Size / Q000235:genetics; D036361:Peptide Hormones / Q000494:pharmacology / Q000502:physiology; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000378:metabolism
D054439:Ghrelin; D036361:Peptide Hormones; D016760:Proto-Oncogene Proteins c-fos; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D043802:GTP-Binding Protein alpha Subunits, Gq-G11