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Analysis of mouse prostate development using serial analysis of gene expression (SAGE) Zhang, Tian-Jiao

Abstract

Mouse prostate organogenesis is initiated with the outgrowth of the urogenital sinus epithelium (UGE) into the surrounding urogenital sinus mesenchyme (UGM). Mesenchymal-epithelial (M/E) interactions are important for prostate development and molecules involved in this process remain to be identified. To enhance our understanding of the molecular mechanisms regulating mouse prostate development, we generated a serial analysis of gene expression (SAGE) library from each of the following six tissues: El6.5 male urogenital sinus (UGS), E16.5 female UGS, E16.5 male UGM, E16.5 male UGE, postnatal day 0 (PO) prostate and adult dorsal-lateral prostate (DLP) libraries. Bioinformatic analyses revealed differential expression of several members of the WNT signaling pathway and expression of some members was confirmed by quantitative Real Time PCR (RT-qPCR). Of particular interest, a gene encoding an antagonist of the WNT pathway known as Secreted Frizzled-Related Protein 2 (SFRP2) was highly expressed in the El6.5 male UGS library and down-regulated in the adult DLP. Transcripts of WNT4, which interact with SFRP2, and P-catenin, a downstream molecule of the canonical WNT pathway, were also differentially expressed in the developing prostate as well as in male and female UGS. Expression patterns of Sfrp2 were examined using both RT-qPCR and Digital Northern analysis. Further, localization of Sfrp2 mRNA and its protein was carried out using in situ hybridization and immunofluorescence, respectively. Our studies show that WNT pathway members are expressed in the developing prostate, suggesting that the WNT pathway may play a role in prostate development. Development of cancer often involves inappropriate reactivation of pathways that are active during normal development. Therefore, expression of Sfrp2, Wnt4 and fi-catenin during prostate cancer (PCa) initiation and progression was evaluated using the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. Sfrp2 and Wnt4 mRNA levels in the TRAMP DLP were upregulated at 4 weeks (PCa initiation) and 8 weeks (PCa progression) of age respectively, compared to their wild type littermates. Taken together, these studies provide the first evidence that WNT pathway members are differentially expressed in the developing prostate and in the DLP of the TRAMP model of PCa. Functional analyses are now required to establish the biological significance of these observations.

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