Inductive signaling interactions between epithelial and mesenchymal cell layers represent one of the principal mechanisms of vertebrate organogenesis. In particular, the prostate arises late in gestation when signals from urogenital sinus mesenchyme induces the urogenital sinus epithelium to form the prostatic buds. Under the influences of androgens, these epithelia buds elongate and undergo ductal morphogenesis, thereby forming the ventral, dorsolateral, and anterior (coagulating gland) lobes of the rodent prostate. The prostate provides an excellent model system for studying inductive epithelial-mesenchymal interactions, the role of androgen signaling in the generation of sexual dimorphism, and the molecular mechanisms of ductal morphogenesis. Moreover, the analysis of prostate development is likely to provide insights into human disease, notably benign prostatic hyperplasia (BPH) and prostate carcinoma. The Principal Investigator has identified a novel homeobox gene, termed Nkx3.1 that appears to play an important regulatory role in prostate development. Nkx3.1 is one of the few transcriptional regulators known to be expressed specifically in the prostate during development and adulthood. Importantly, the preliminary analysis of Nkx3.1 null phenotype has demonstrated that Nkx3.1 is required for normal prostate development and function. The regulatory role of Nkx3.1 in prostate development will be investigated by performing a detailed analysis of its biochemical properties, expression pattern, cellular activities, and biological functions as follows: 1) the biochemical properties of the Nkx3.1 protein will be analyzed by examining its requirements for DNA recognition, its transcriptional properties, and its post-translational modification by phosphorylation; 2) the expression pattern and cellular functions of Nkx3.1 will be analyzed by examining the distribution of murine Nkx.3.1 transcripts and protein in the male urogenital system, and investigating the effects of Nkx3.1 on cell proliferation and transformation; and 3) the biological role of Nkx3.1 in development will be analyzed by investigating its role in the male urogenital system, by examining its cell autonomy, and its over-expression in reconstituted prostatic tissue.
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