Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 41, Pages 14794-14799Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0405091101
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Funding
- NIAMS NIH HHS [R01 AR047078, AR47078] Funding Source: Medline
- NIDDK NIH HHS [DK56246, DK46718, P01 DK056246, R01 DK046718, R56 DK046718, R37 DK046718] Funding Source: Medline
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Stimulatory heterotrimeric G protein (Gs) transduces signals from various cell-surface receptors to adenylyl cyclases, which generate cAMP. The a subunit of Gs (Gsalpha) is encoded by GNAS (Gnas in mice), and heterozygous Gsa inactivating mutations lead to Albright hereditary osteodystrophy. The in vivo role of Gsa in skeletogenesis is largely unknown, because of early embryonic lethality of mice with disruption of Gnas exon 2 (Gnas(E2-)/E2-) and the absence of easily detectable phenotypes in growth plate chondrocytes of heterozygous mutant mice (Gnas(+)/(E2-)). We generated chimeric mice containing wild-type cells and either Gnas(E2-)/(E2-) or Gnas(+/E2-) cells. Gnas(E2-)/(E2-) chondrocytes phenocopied PTH/PTHrP receptor (PPR)(-/-) cells by prematurely undergoing hypertrophy. Introduction of a transgene expressing Gsa, one of several gene products that include Gnas exon 2, into Gnas(E2-)/(E2-) cells prevented premature hypertrophy. Gsa mRNA expression detected by real-time RT-PCR analysis was reduced to approximately half that of the wild-type in both paternal and maternal Gnas(+)/(E2-) growth plate chondrocytes, indicating biallelic expression of Gsa in these cells. Hypertrophy of Gnas(+)/(E2-) chondrocytes was modestly but significantly premature in chimeric growth plates of mice containing wild-type and Gnas(+)/(E2-) cells. These data suggest that Gsa is the primary mediator of the actions of PPR in growth plate chondrocytes and that there is haploinsufficiency of Gsa signaling in Gnas(+)/(E2-) chondrocytes.
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