application) Infertility, which is experienced by 15 percent of couples, presents a significant public health concern. Causes of reproductive impairment are not well understood but include genetic, nutritional, and other environmental factors. A growing number of genes are known to be involved in proper formation and function of genitourinary tissues, but little is known about their regulation during development and cell differentiation. The research proposed here focuses on the discovery and identification of new regulatory elements, such as promoters and enhancers, which are active in cells of the developing and adult genitourinary system. Analysis of a targeted mutation of the mouse gene Punc revealed a phenotype of hypogonadism and infertility in male mice. The human Punc gene maps to the critical region of Bardet-Biedl Syndrome 4, where male hypogonadism is part of the phenotype. Closer inspection of the chromosomal area, in mouse and human, showed that Punc is located within a cluster of four closely spaced genes, one of which is similar to Punc, and two more that are novel. All four genes are expressed in the genitourinary system. With the mouse as experimental model, we propose to identify the control elements for these four genes by using a novel version of the reporter gene approach. We combine a library concept for the production of constructs, high-throughput transfections and reporter gene assays in tissue culture, and in vivo studies in transgenic mice. Choice of cell lines centers this strategy on the cell types of the genitourinary system. This technology makes it feasible to screen large genomic areas for the presence of functional control elements. Such an approach will not only lead to mechanistic understanding of gene regulation in genitourinary development and function, but will have impact for the genome view on gene regulation
| Kappen, Claudia; Salbaum, J Michael (2009) Identification of regulatory elements in the Isl1 gene locus. Int J Dev Biol 53:935-46 |
| Han, Sang Jun; Jeong, Jaewook; Demayo, Francesco J et al. (2005) Dynamic cell type specificity of SRC-1 coactivator in modulating uterine progesterone receptor function in mice. Mol Cell Biol 25:8150-65 |
