title: Postnatal changes in the expression pattern of the imprinted signalling protein XLαs underlie the changing phenotype of deficient mice.
abstract: The alternatively spliced trimeric G-protein subunit XLαs, which is involved in cAMP signalling, is encoded by the Gnasxl transcript of the imprinted Gnas locus. XLαs deficient mice show neonatal feeding problems, leanness, inertia and a high mortality rate. Mutants that survive to weaning age develop into healthy and fertile adults, which remain lean despite elevated food intake. The adult metabolic phenotype can be attributed to increased energy expenditure, which appears to be caused by elevated sympathetic nervous system activity. To better understand the changing phenotype of Gnasxl deficient mice, we compared XLαs expression in neonatal versus adult tissues, analysed its co-localisation with neural markers and characterised changes in the nutrient-sensing mTOR1-S6K pathway in the hypothalamus. Using a newly generated conditional Gnasxl lacZ gene trap line and immunohistochemistry we identified various types of muscle, including smooth muscle cells of blood vessels, as the major peripheral sites of expression in neonates. Expression in all muscle tissues was silenced in adults. While Gnasxl expression in the central nervous system was also developmentally silenced in some midbrain nuclei, it was upregulated in the preoptic area, the medial amygdala, several hypothalamic nuclei (e.g. arcuate, dorsomedial, lateral and paraventricular nuclei) and the nucleus of the solitary tract. Furthermore, expression was detected in the ventral medulla as well as in motoneurons and a subset of sympathetic preganglionic neurons of the spinal cord. In the arcuate nucleus of Gnasxl-deficient mice we found reduced activity of the nutrient sensing mTOR1-S6K signalling pathway, which concurs with their metabolic status. The expression in these brain regions and the hypermetabolic phenotype of adult Gnasxl-deficient mice imply an inhibitory function of XLαs in energy expenditure and sympathetic outflow. By contrast, the neonatal phenotype of mutant mice appears to be due to a transient role of XLαs in muscle tissues.
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Krechowec
authors.forename: Katie L
authors.initials: KL
authors.lastname: Burton
authors.forename: Anna U
authors.initials: AU
authors.lastname: Newlaczyl
authors.forename: Nicolas
authors.initials: N
authors.lastname: Nunn
authors.forename: Nikolina
authors.initials: N
authors.lastname: Vlatković
authors.forename: Antonius
authors.initials: A
authors.lastname: Plagge
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D002864:Chromogranins; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D018390:Gene Targeting; D056426:Genetic Loci / Q000235:genetics; D018392:Genomic Imprinting / Q000187:drug effects / Q000235:genetics*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002864:Chromogranins; D007328:Insulin; D020738:Leptin; D009479:Neuropeptides; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs