Versatile model for conditional prostate gene expression

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DESCRIPTION (provided by applicant): An increasing body of evidence points to alterations in the expression and function of growth factors and hormones or their receptors in the etiology of prostate disease. The availability of appropriate animal models would greatly facilitate 'efforts to determine which changes in gene expression observed in human prostate disease are relevant to disease initiation and progression. The only mammalian system where it is currently feasible and practical to examine the effects of both gain and loss of function mutations in specific genes is the mouse. The technical sophistication of the systems that permit the addition or deletion of genes to the mouse genome have progressed to the point where it is now possible to generate nearly any genetic alteration that can be envisioned, from point mutation to large-scale deletion. Using the bacteriophage P 1 Cre-lox recombination system, these changes can be imparted in a tissue-specific manner, provided that cis-acting elements capable of directing Cre recombinase expression in the appropriate tissue have been defined. The development and validation of transgenic mouse strains that express constitutively active and inducible forms of Cre in prostate epithelial cells is therefore a high priority. Existing strains of mice that express Cre in a prostate restricted manner produce functional Cre in the majority of luminal epithelial cells. Although these mice allow for prostate restricted manipulation of genes, the high frequency of recombination events that occur in these mice do not permit modeling of focal genetic changes similar to those that are likely to occur in human prostate tissue. The objective of the work proposed here is to develop strains of transgenic mice that reproducibly express the Cre recombinase in a percentage of prostate epithelial cells that varies from a few cells to nearly all. We propose to generate strains of mice that express either the natural form of Cre or an inducible form that can be activated at will. This goal will be achieved by generating strains of transgenic mice carrying Cre genes under the control of nkx-3.1 cis-regulatory regions. The function of Cre will be validated by mating the nkx-3.1/cre transgenic mice to a reporter strain of mice in which activation of a Beta-galactosidase gene is dependent on Cre excision. The transgenic mice we propose to generate will be extremely useful to study the effects of deletion or activation of any gene in the development or progression of prostate disease. With a complete sequence of the human genome in hand, we are poised to begin a systematic molecular dissection of prostate disease etiology. Our ability to test gene function in a tissue-specific manner in transgenic mice will be a critical component of that process.