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Abstract

Characterization of a novel gain of function glucocorticoid receptor knock-in mouse (PDF) (HTML) 
Zhang,Junhui; Ge,Renshan; Matte-Martone,Catherine; Goodwin,Julie; Shlomchik,Warren D.; Mamula,Mark J.; Kooshkabadi,Ali; Hardy,Matthew P.; Geller,David
Journal of Biological Chemistry 284(10): 6249-6259
Publication date: 2009

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Glucocorticoids (GCs) exert profound influences on many physiologicfunctions by virtue of their diverse roles in growth, development,and maintenance of homeostasis. We previously created a novelgain of function in the human glucocorticoid receptor (hGR),hGR, which is active at GC concentrations 5-10-foldlower than wild-type GR. To gain a greater insight into GC physiologyin vivo, we inserted this mutant GR (GR in mice) into micevia homologous recombination. Mice expressing the allele arephenotypically normal with respect to GC function. However,corticosterone levels, ACTH levels, and adrenocortical sizeare markedly reduced, suggesting they are phenotypically normalbecause the mutant GR alters the basal regulation of the hypothalamic-pituitary-adrenalaxis. We demonstrate via physiologic and immunologic studiesthat GR mice have increased sensitivity to GCs in vivo.Sensitivity to the actions of endogenous GCs may be an importantfactor underlying the development of many human diseases includinghypertension, obesity, and diabetes. Our model may provide anew and powerful tool for the study of GC physiological andpathological processes in vivo.

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