Transforming growth factor-beta 2 heterozygous mutant mice exhibit Cowper's gland hyperplasia and cystic dilations of the gland ducts (Cowper's syringoceles).
ABSTRACT Analyses of mutant mice with a deletion for the transforming growth factor beta 2 (Tgfbeta2) gene revealed cysts in the perineal/scrotal region of male mice. We present evidence from in situ, light and electron microscopy that the cysts observed in Tgfbeta2+/- heterozygous mice males derive from Cowper's gland tissue. The Cowper's glands of Tgfbeta2+/- heterozygous mutant mice display all steps of glandular hyperplasia and cystic dilation. TGF-beta isoforms and TGF-beta receptor (TbetaR-II) were localized immunocytochemically in sections of Cowper's glands. TGF-beta2 and TGF-beta3 were located predominantly in myoepithelial cells of the Cowper's gland whereas the TbetaRII was found in the plasma membrane of the acinar cells. TUNEL-assays revealed that apoptotic cell death is significantly reduced in Cowper's glands of TgfbetaB2+/- heterozygous mutant mice. The fact that Tgfbeta2+/- heterozygous mutant mice exhibit hyperplasia of Cowper's gland epithelium and Cowper's gland cysts suggests a disturbance of epithelial-stromal interaction most likely due to reduced TGF-beta2 level, accompanied by a significant decrease in apoptosis.
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ABSTRACT: Programmed cell death (PCD) is a key phenomenon in the regulation of cell number in multicellular organisms. We have shown that reduction of endogenous transforming growth factor beta (TGF-beta) prevents apoptotic PCD of neurons in the developing peripheral and central nervous system, suggesting that TGF-beta is an important mediator of ontogenetic neuron death. Previous studies suggested that there are other pro-apoptotic molecules, nerve growth factor (NGF) and brain-derived neurotrophic factor, that induce cell death in the nervous system. In the developing chick retina, NGF induces PCD by activation of the p75 receptor. We have studied the role of TGF-beta and its putative interdependence with NGF-mediated PCD in the chick retina. We found that TGF-beta is present in the developing chick retina during the period of PCD and is essentially required to regulate PCD of retinal cells. TGF-beta 2, TGF-beta 3 and the ligand-binding TGF-beta receptor can be detected immunocytochemically in the central retina, a region where apoptosis is most prominent during the early period of PCD. Application of a TGF-beta-neutralizing antibody to chick embryos in ovo resulted in a decrease in the number of TUNEL-positive cells and a reduction of free nucleosome levels. In terms of magnitude, reduction of PCD caused by the neutralization of endogenous TGF-beta was equivalent to that seen after anti-NGF application. Neutralization of both factors did not result in a further decrease in apoptosis, indicating that NGF and TGF-beta may act on the same cell population. Furthermore, neutralization of TGF-beta did not affect the expression of NGF or the p75-receptor. Our results suggest that TGF-beta and NGF are both required to regulate cell death in the chick retina in vivo.Development 07/2001; 128(11):1933-42. · 6.60 Impact Factor