Oxytocin is a nonapeptide hormone that participates in the regulation of parturition and lactation. It has also been implicated in various behaviors, such as mating and maternal, and memory. To investigate whether or not oxytocin (OT) is essential for any of these functions, we eliminated, by homologous recombination, most of the first intron and the last two exons of the OT gene in mice. Those exons encode the neurophysin portion of the oxytocin preprohormone which is hypothesized to help in the packaging and transport of OT. The homozygous mutant mice have no detectable neurophysin or processed oxytocin in the paraventricular nucleus, supraoptic nucleus or posterior pituitary. Interestingly, homozygous mutant males and females are fertile and the homozygous mutant females are able to deliver their litters. However, the pups do not successfully suckle and die within 24 h without milk in their stomachs. OT injection into the dams restores the milk injection in response to suckling. These results indicate an absolute requirement for oxytocin for successful milk injection, but not for mating, parturition and milk production, in mice.
The genes for the posterior pituitary hormones oxytocin (OT) and vasopressin (VP) are expressed in magnocellular neurons of the hypothalamus. Previous attempts to obtain cell-specific expression of OT and VP transgenes in mice have been unsuccessful using constructs containing only the OT or VP genes. As the endogenous genes are located near each other on the same chromosome, we investigated four transgenic mouse lines incorporating a single 5.2 k bp construct of rat genomic deoxyribonucleic acid with 1.63 k bp and 3.55 k bp of the OT and VP genes, respectively. Rat OT transcripts were detected only in transgenic mouse OT neurons of the paraventricular and supraoptic nuclei in two lines. The levels of endogenous and transgene OT transcripts increased in response to 10 days of lactation. Furthermore, rat OT-associated neurophysin immunoreactivity was detected in magnocellular cell bodies as well as in the posterior pituitary of the transgenic but not the control mice. Cell-specific rat VP expression was not detected in these transgenic mice.The oxytocin (OT) and vasopressin (VP) genes code for related nonapeptides that participate in the regulation of parturition and lactation, and fluid balance, respectively (1). Transcripts encoding the preprohormones are made primarily in separate populations of magnocellular neurons of the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. The preprohormones are processed into OT or VP and associated neurophysins (NP-OT, NP-VP) during axonal transport to the posterior pituitary where the products are secreted into the circulation (2). O T mRNA and serum peptide levels increase with parturition, lactation, and, along with VP mRNA and serum peptide levels, with hyperosmolality (reviewed in (I) and (3)).Little is known about factors that trans-activate the OT gene or cis-acting sequences (response elements) that allow control of expression. An estrogen responsive element has been detected in the human OT S'-flanking region between bases -164 and -1 15 (4). Similar elements in rat and human OT 5'-flanking regions have also been described by Burbach et al. (5). The latter authors detected no estrogen receptors or changes in OT mRNA levels there following ovariectomy and replacement with estradiol, although Miller et al. (6) described lower levels in ovariectomized or prepubescent female rats. In addition, OT neurons concentrate estradiol (7).Interactions between trans-acting factors and response elements found in vitro need to be validated in vivo. Transgenic animals have been used for this purpose (8). To date, however, few attempts have been made to study the expression of OT in transgenic mice. Carter and colleagues produced transgenic mice that contained 4.2 k bp of bovine genomic DNA, including the OT transcriptional unit and 0.6 k bp upstream (9). No bovine OT expression was detected in the mouse hypothalamus, but there was ectopic expression in the cerebellum, lung and testis. The cell-specific regulation of VP expression is also not understood. ...
Hyperosmotic stimuli produce profound changes in cellular morphology and biosynthetic activities within the hypothalamic paraventricular and supraoptic nuclei (SON) of the rat. The mechanisms by which osmoreceptive signals are transduced within these nuclei are poorly understood. We examined several components of the cAMP-associated second messenger system after giving rats 2% saline to drink for one week, a strong hyperosmotic stimulus. We found that mRNA levels for both the stimulatory and inhibitory guanine-nucleotide binding protein alpha-subunits were increased in the paraventricular nucleus and SON. In the SON, these changes were accompanied by increased basal cAMP levels, cholera toxin-stimulated adenylate cyclase, and Gs alpha. Our results suggest that Gs alpha levels are not saturated with respect to adenylate cyclase coupling and that osmoreception activates the cAMP second messenger system.
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