Abstract
Gene expression and functional studies have indicated that the molecular programmes involved in prostate development are also active in prostate cancer. PTEN has been implicated in human prostate cancer and is frequently mutated in this disease. Here, using the Nkx3.1:Cre mouse strain and a genetic deletion approach, we investigate the role of Pten specifically in the developing mouse prostate epithelia. In contrast to its role in other developing organs, this gene is dispensable for the initial developmental processes such as budding and branching. However, as cytodifferentiation progresses, abnormal luminal cells fill the ductal lumens together with augmented epithelial proliferation. This phenotype resembles the hyperplasia seen in postnatal Pten deletion models that develop neoplasia at later stages. Consistent with this, gene expression analysis showed a number of genes affected that are shared with Pten mutant prostate cancer models, including a decrease in androgen receptor regulated genes. In depth analysis of the phenotype of these mice during development revealed that loss of Pten leads to the precocious differentiation of epithelial cells towards a luminal cell fate. This study provides novel insight into the role of Pten in prostate development as part of the process of coordinating the differentiation and proliferation of cell types in time and space to form a functional organ.
Highlights
The mammalian prostate is a male specific structure that develops from the urogenital sinus under the influence of androgens [1]
We have used a Cre expressing strain of mice that deletes Pten in the majority of prostate epithelia cells as they arise during embryogenesis
This is in contrast to other studies using Cre expressing lines such as the PSA-Cre and PbCre4, where Pten is deleted in a subset of prostate epithelial cells starting after postnatal stages and mostly found in luminal cells
Summary
The mammalian prostate is a male specific structure that develops from the urogenital sinus under the influence of androgens [1]. Androgen dependent signals from the mesenchyme induce the budding of the urogenital sinus epithelium, which become visible around 17.5 days of embryonic development (E17.5). The epithelial prostatic buds grow out into the surrounding mesenchyme and go through the processes of branching morphogenesis, canalization and cytodifferentiation into basal and luminal cells. These, together with rare neuroendocrine cells give rise to a fully functional adult organ. Gene expression studies have indicated that molecular programmes that are specific to prostate development are active in prostate cancer [2,3]. Analyses of pathways during organ development have provided important information as to the role of signalling molecules in prostate neoplasia
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