Over-expression of oxytocin in the testes of a transgenic mouse model

Abstract

The bovine oxytocin gene has been expressed in the testes of two independent transgenic mouse lines. Hybridization and RNase protection analysis showed that the oxytocin transgene was transcribed from the normal functional promoter in the Sertoli cells of the seminiferous tubules in a developmentally regulated manner. Immunohistochemistry indicated that both oxytocin and neurophysin epitopes were expressed together in the Sertoli cells at stages I\p=n-\Vand X\p=n-\XIIof the cycle of the seminiferous epithelium. Furthermore, analysis with high-performance liquid chromatography showed that there was a tenfold increase in the amount of amidated oxytocin present in testicular extracts from the transgenic mice. However, there appeared to be no detectable effect of this overproduction of hormone on testicular morphology or fertility parameters. A significant decrease by 50% was detected only in the levels of intratesticular testosterone and dihydrotestosterone. The results point to a local paracrine role for oxytocin in the modulation of Leydig cell function.

Two orphan receptors binding to a common site areinvolved in the regulation of the oxytocin gene in the bovineovary.

“…The peripheral expression of the bovine oxytocin-gene is not restricted to the female gonad but is also appreciable within the Sertoli cells in the testis of the bull and of transgenic mice carrying the bovine oxytocin gene with only 600 bp of the promoter region (6). As the Ii cell line established from bovine granulosa cells apparently had shut off the expression of the endogenous oxytocin gene during tissue culture (data not shown) the mouse testicular cell line TM4, supposedly of Sertoli cell origin (28), was chosen to investigate the regulation of oxytocin gene expression by transient-transfection studies.…”

“…In particular, it is highly up-regulated in the large cells of the early bovine corpus luteum, which are derived by luteinization of preovulatory granulosa cells (5), and in the bovine testis (6). A transgenic study using a bovine oxytocin gene construct comprising only the gene and 600 bp of the 5' noncoding sequence indicated consistent expression in the Sertoli cells of the transgenic mouse, evidently using the same transcription start site as in the hypothalamus or as in the bovine ovary and testis (6). These observations suggest that, unlike in the hypothalamus, the bovine oxytocin gene can be tissue-specifically expressed in the gonads by a minimal functional promoter contained within 600 bp of the transcription start site.…”

Transgenic mice in the analysis of reproductive development and function

“…et al (1995) bcl-2 knockout Histologically abnormal primordial follicles Ratts et al (1995) Prostaglandin synthase 1 knockout Decreased live offspring from homozygous cross homozygous matings Langenbach et al (1995) Human FSHβ gene transgenic Increased chimaeric mouse/human FSH but no reproductive defects Kumar et al (1992) Bovine oxytocin gene transgenic Normal fertility but decreased testicular androgens Ang et al (1994) MT-transforming growth factor α Modulatory role of TGFα in the hypothalamus and ovary Ma et al (1994) Bovine FSHβ promoter-HSV-tk Normal fertility despite decreased FSH/LH Markkula et al (1995) Bovine glycoprotein α promoter-HSV-tk Normal fertility, although some males showed decreased testis size Camper et al (1995) PGK-cmos Normal fertility; increased germ cell number Higgy et al (1995) Rat probasin promoter-SV40 T antigen Prostate neoplasia Greenberg et al (1995) Human glycoprotein hormone α subunit Pituitary gonadotroph (α subunit secreting) tumours Windle et al (1990) Inhibin α promoter-SV40 T-Ag Granulosa cell tumours; Leydig cell tumours Kananen et al (1995) Similar to the case in humans, the development of these tumours usually results in secondary infertility. As mentioned above, human GnRH promoter-SV40 T antigen transgenic mice develop tumours in the hypothalamus along the normal course of migration of the GnRH neurones (Table 4; Radovick et al, 1991).…”

Alterations in the Chromatin Structure of the Distal Promoter Region of the Bovine Oxytocin Gene Correlate with Ovarian Expression

“…sary for transcriptional control and correct initiation of tran¬ scription (Ang et al, 1994), but is not alone sufficient for tis¬ sue-specific up-regulation of oxytocin expression. Computer searches for transcription factor binding sites as well as transient transfection studies can be used to identify sequences that may be involved in the control of oxytocin expression, but alone cannot provide conclusive evidence that these regions really are necessary for transcriptional control in vivo.…”