The mouse seminal vesicle shape mutation is allelic with Fgfr2.

The mouse seminal vesicle shape (svs) mutation is a spontaneous recessive mutation that causes branching morphogenesis defects in the prostate gland and seminal vesicles. Unlike many other mutations that reduce prostatic and/or seminal vesicle branching, the svs mutation dramatically reduces branching without reducing organ growth. Using a positional cloning approach, we identified the svs mutant lesion as a 491 bp insertion in the tenth intron of Fgfr2 that results in changes in the pattern of Fgfr2 alternative splicing. An engineered null allele of Fgfr2 failed to complement the svs mutation proving that a partial loss of FGFR2(IIIb) isoforms causes svs phenotypes. Thus, the svs mutation represents a new type of adult viable Fgfr2 allele that can be used to elucidate receptor function during normal development and in the adult. In the developing seminal vesicles, sustained activation of ERK1/2 was associated with branching morphogenesis and this was absent in svs mutant seminal vesicles. This defect appears to be the immediate downstream effect of partial loss of FGFR2(IIIb) because activation of FGFR2(IIIb) by FGF10 rapidly induced ERK1/2 activation, and inhibition of ERK1/2 activation blocked seminal vesicle branching morphogenesis. Partial loss of FGFR2(IIIb) was also associated with down-regulation of several branching morphogenesis regulators including Shh, Ptch1, Gli1, Gli2, Bmp4, and Bmp7. Together with previous studies, these data suggest that peak levels of FGFR2(IIIb) signaling are required to induce branching and sustain ERK1/2 activation, whereas reduced levels support ductal outgrowth in the prostate gland and seminal vesicles.

Markers of prostate region-specific epithelial identity define anatomical locations in the mouse prostate that are molecularly similar to human prostate cancers.

Although the basic functions of the prostate gland are conserved among mammals, its morphology varies greatly among species. Comparative studies between mouse and human are important because mice are widely used to study prostate cancer, a disease that occurs in a region-restricted manner within the human prostate. An informatics-based approach was used to identify prostate-specific human genes as candidate markers of region-specific identity that might distinguish prostatic ducts prone to prostate cancer from ducts that rarely give rise to cancer. Subsequent analysis of normal and cancerous human prostates demonstrated that the genes microseminoprotein-beta (MSMB) and transglutaminase 4 (TGM4) were expressed in distinct groups of ducts in the normal human prostate, and only MSMB was detected in areas of prostate cancer. The mouse orthologs of MSMB and TGM4 were then used for expression studies in mice along with the mouse ventrally expressed gene spermine binding protein (SBP). All three genes were informative markers of region-specific epithelial identity with distinct expression patterns that collectively accounted for all ducts in the mouse prostate. Together with the human data, this suggested that MSMB expression defines an anatomical domain in the mouse prostate that is molecularly most similar to human prostate cancers. Computer-assisted serial section reconstruction was used to visualize the complete expression domains for MSMB, SBP, and TGM4 in the mouse prostate. This showed that MSMB is expressed in prostatic ducts that comprise 21% of the mouse dorso-lateral prostate. Finally, the expression of MSMB, SBP, and TGM4 was evaluated in a mouse prostate cancer model created by the prostate epithelium-specific deletion of the tumor suppressor PTEN. MSMB and TGM4 were rapidly and dramatically down-regulated in response to PTEN deletion suggesting that this model of prostate cancer includes a more rapid de-differentiation of the prostatic epithelium than is observed in organ-confined human prostate cancers.