Pituitary-specific knockout of the Carney complex gene Prkar1a leads to pituitary tumorigenesis.
Carney complex (CNC) is an inherited neoplasia syndrome characterized by spotty skin pigmentation, myxomas, endocrine tumors, and schwannomas. Among the endocrine tumors that comprise the syndrome, GH-producing pituitary tumors are seen in approximately 10% of patients, although biochemical abnormalities of the GH axis are much more common. To explore the role of loss of the CNC gene PRKAR1A on pituitary tumorigenesis, we produced a tissue-specific knockout (KO) of this gene in the mouse. For these studies, we generated a mouse line expressing the cre recombinase in pituitary cells using the rat GHRH receptor promoter. These mice were then crossed with Prkar1a conditional null animals to produce tissue-specific KOs. Although prolactinomas were observed in KO and control mice, the KO mice exhibited a significantly increased frequency of pituitary tumors compared with wild-type or conventional Prkar1a(+/-) mice. Characterization of the tumors demonstrated they were composed of cells of the Pit1 lineage that stained for GH, prolactin, and TSH. At the biochemical level, levels of GH in the serum of KO animals were markedly elevated compared with controls, regardless of the presence of a frank tumor. These data indicate that complete loss of Prkar1a is sufficient to allow the formation of pituitary tumors and abnormalities of the GH axis, in close analogy to human patients with CNC.
Yin
Zhirong
Z
Department of Molecular Virology, Immunology, and Molecular Genetics, The Ohio State University, 420 West 12th Avenue, Columbus, OH 43210, USA.
Williams-Simons
Lisa
L
Parlow
A F
AF
Asa
Sylvia
S
Kirschner
Lawrence S
LS
D000818:Animals; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D013006:Growth Hormone / Q000097:blood; D007150:Immunohistochemistry; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D010902:Pituitary Gland / Q000378:metabolism* / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology; D011388:Prolactin / Q000097:blood; D015175:Prolactinoma / Q000097:blood / Q000235:genetics / Q000473:pathology; D013972:Thyrotropin / Q000097:blood
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse; D011388:Prolactin; D013972:Thyrotropin; D013006:Growth Hormone; C045073:Cre recombinase; D019426:Integrases