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Regulable Expression of Inhibin A in Wild-Type and Inhibin Null Mice

Department of Molecular and Cellular Biology (T.M.P., F.J.D., M.M.M., S.Y.T., B.W.O.) Department of Pathology (M.M.M.), and Department of Molecular and Human Genetics (M.M.M.) Baylor College of Medicine Houston, Texas 77030
Schering-Plough Corp. Research Institute (Y.W.) Kenilworth, New Jersey 07033

Exogenous regulation of protein expression creates the potential to examine the consequences of homeostatic Dysregulation in many physiological systems and, when used in transgenic mice, provides the capability of restoring a gene product to its knockout background without antigenicity issues. In this study, we used a mifeprisone-inducible system (the GeneSwitch system) to regulate the expression of inhibin A from the liver of mice. Inhibin is a heterodimeric protein (/ß) wherein one of its subunits (ß) is capable of homodimerizing to form its physiological antagonist, activin (ß/ß). Inhibin is also expressed in two forms, A and B, as determined by the subtype of ß-subunit that dimerizes with the -subunit (/ßA or /ßB). To utilize the GeneSwitch system, transgenic transactivator mice with liver-specific expression of a mifepristone-activated chimeric nuclear receptor (GLVP) were crossed with transgenic target mice containing a GVLP-responsive promoter upstream of poliovirus IRES (internal ribosome entry site)-linked sequences coding for the - and ß-subunits of inhibin A. This intercross produced "bigenic" mice capable of regulable expression of inhibin A from the liver. Overexpression of inhibin A in wild-type mice produced a phenotype wherein males had decreased testis size and females had a block in folliculogenesis at the early antral stage, findings similar to activin type IIA receptor (ActRIIA) null mice. These phenotypes were most likely due to suppressed serum FSH, confirming that the liver-derived inhibin A was secreted into the serum to down-regulate pituitary FSH levels. Furthermore, the generation of bigenic mice in the inhibin null background allowed for the induction of inhibin A in inhibin null male mice with subsequent rescue of these mice from their gonadal tumor-induced lethal phenotype. This work demonstrates the in vivo production of a heterodimeric hormone from a single inducible promoter to study its therapeutic and physiological effects. In addition, these studies are the first example of an inducible system being used to prevent a lethal knockout phenotype in an animal model.

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