Skeletal abnormalities and extra-skeletal ossification in mice with restricted Gsalpha deletion caused by a renin promoter-Cre transgene.
We have recently generated a transgenic mouse line (termed hRen-Cre) that expresses Cre-recombinase under the control of a 12.2-kb fragment of the human renin promoter. In the present study, we have crossed hRen-Cre mice with a mouse strain in which exon 1 of the Gnas gene is flanked by loxP sites. Gnas encodes the alpha-subunit of the stimulatory G protein (Gs alpha). Our aim has been to generate a mouse model with locally restricted inactivation of Gs alpha to extend studies of the role of Gs alpha function in vivo. Mice with local Cre-mediated inactivation of Gs alpha (rCre-Gs alpha) are viable and fertile. Their most obvious phenotype consists of marked skeletal malformations of the forelimbs in which computer-tomography scans reveal shortened and fused extremity bones. Extraskeletal ossifications occur in the subcutis and in skeletal muscles associated with the affected long bones. Plasma calcium, phosphate and parathyroid hormone are normal. Skin histology has demonstrated diffuse mineralization and ossification associated with the basal cells of hair follicles. This phenotype in part resembles syndromes in humans associated with loss-of-function of Gs alpha, such as Albright hereditary osteodystrophy and progressive osseous heteroplasia. The renal phenotype of rCre-Gs alpha mice is inconspicuous. Plasma renin concentration, ambient urine osmolarity, and the glomerular filtration rate of rCre-Gs alpha mice do not differ from controls. The absence of measurable functional changes in the renin-angiotensin system indicates insufficient Cre expression in juxtaglomerular granular cells in this strain of mice. Nevertheless, the present report reaffirms the importance of Gs alpha signaling for bone development and the suppression of ectopic ossification.
Castrop
Hayo
H
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. hayo@castrop.com
Oppermann
Mona
M
Mizel
Diane
D
Huang
Yuning
Y
Faulhaber-Walter
Robert
R
Weiss
Yvonne
Y
Weinstein
Lee S
LS
Chen
Min
M
Germain
Stephane
S
Lu
Huiyan
H
Ragland
Dan
D
Schimel
Daniel M
DM
Schnermann
Jurgen
J
D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities* / Q000502:physiology; D002864:Chromogranins; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000502:physiology; D006801:Humans; D019426:Integrases / Q000235:genetics*; D007606:Juxtaglomerular Apparatus / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009999:Ossification, Heterotopic / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012083:Renin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000502:physiology; D015398:Signal Transduction; D019076:Transgenes
D002864:Chromogranins; C045073:Cre recombinase; D019426:Integrases; D012083:Renin; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs