Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation

Abstract

To facilitate the elucidation of the genetic events that may play an important role in the development or tumorigenesis of the prostate gland, we have generated a transgenic mouse line with prostate-specific expression of Cre recombinase. This line, named PB-Cre4, carries the Cre gene under the control of a composite promoter, ARR2PB which is a derivative of the rat prostate-specific probasin (PB) promoter. Based on RT-PCR detection of Cre mRNA in PB-Cre4 mice or Cre-mediated activation of LacZ activity in PB-Cre4/R26R double transgenic mice, it is conclusively demonstrated that Cre expression is post-natal and prostatic epithelium-specific. Although the Cre recombination is detected in all lobes of the mouse prostate, there is a significant difference in expression levels between the lobes, being highest in the lateral lobe, followed by the ventral, and then the dorsal and anterior lobes. Besides the prostate gland, no other tissues of the adult PB-Cre4 mice demonstrate significant Cre expression, except for a few scattered areas in the gonads and the stroma of the seminal vesicle. By crossing the PB-Cre4 animals with floxed RXRalpha allelic mice, we demonstrate that mice, whose conventional knockout of this gene is lethal in embryogenesis, could be propagated with selective inactivation of RXRalpha in the prostate. Taken together, the results show that the PB-Cre4 mice have high levels of Cre expression and a high penetrance in the prostatic epithelium. The PB-Cre4 mice will be a useful resource for genetic-based studies on prostate development and prostatic disease.

Prostate targeting: PSP94 gene promoter/enhancer region directed prostate tissue-specific expression in a transgenic mouse prostate cancer model

“…However, its targeting to non-prostate tissues has also been reported. 24 Recently, an osteocalcin promoter was used in a novel strategy for cotargeting both tumor epithelial and bone stromal cells in gene therapy of androgen-independent CaP bone metastasis. 25,26 Current gene therapy clinical trials of prostate cancer utilize a combination of the only two available targeting vector genes with both the rat probasin promoter sequence and human PSA promoter sequence 13,20,27 without the benefit of prior testing in an appropriate transgenic animal model.…”

Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition

“…The development of murine prostate cancer models, however, is severely hindered by a lack of spontaneous tumor development within the mouse prostate. Several models of murine prostate cancer exist, including those generated through the use of prostate tissue specific promoters to drive expression of the SV40 small t and/or large T antigens [4,5], or the development of transgenics with conditional knockouts [6] or hemizygous knockouts [7]. Another model, the mouse prostate reconstitution model (MPR) developed by retro-viral infection of murine urogenital sinus for the expression of activated oncogenes [8], has been effectively used in immunotherapy studies of prostate cancer [9,10].…”

Reduced prostate branching morphogenesis in stromal fibroblast, but not in epithelial, estrogen receptor α knockout mice

“…It has been well known that the mouse prostate undergoes extensive branching morphogenesis during the first 15 days of life. 30 Probasin promoter-driven Cre excision is barely detectable in the prostate during the first 15 days of neonatal mice, 37 which could be the reason that we did not observe the changes in the pes-ERaKO prostate development. In order to further define the role of epithelial ERa in the early prostatic development, the use of NKX3.1 Cre could be an ideal strategy, because its Cre activity begins to express at embryonic stage E17.5 in a prostatic epithelium-specific manner.…”

“…The promoter of probasin is well characterized and widely applied in many animal models. [37][38][39] The expression of probasin Cre (PB-Cre) is prostatic epithelial-specific and is postnatal and gradually increased with highest expression in the lateral lobe, followed by the VP, and then the DP and AP. 37,38 Therefore, PB-Cre can specifically knock out the floxed ERa gene in prostate epithelial cells (pes-ERaKO).…”