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- Differential expression of WNT4 in testicular and ovarian development in a marsupial

We report the first molecular characterization and expression pattern of WNT4 in a non-eutherian mammal, the tammar wallaby. This is also the first localization of WNT4 protein in the gonad of any mammal. The greatly extended developmental time of marsupial gonads enabled us to complete the first detailed analysis of the changes in WNT4 expression throughout the whole of this critical developmental period. Since the mouse testis undergoes rapid development, the period of WNT4 down-regulation that we have observed in the tammar testis occurs very rapidly in the mouse and so may have been missed. In the female, WNT4 is upregulated during the time of ovarian differentiation, but is down-regulated by the time the XX germ cells have all entered meiosis. In the male, it is down-regulated by the day of birth when testicular differentiation is occurring, but gradually increases by the time XY germ cells have all entered mitotic arrest. The conserved but differing expression patterns of WNT4 in the wallaby ovary and testis supports the idea that it has a critical role in gonadal development in both sexes.

The structure and role of WNT gene family is highly conserved in vertebrates [36,37], and even in the sea anemone, a species representing the basal group within cnidarians [38]. However, the full-length WNT4 gene sequence has only been previously characterized in three mammals, and four non-mammalian vertebrates (Fig. 1). The tammar WNT4 gene consists of five exons, exons 2 – 4, the most highly conserved. The tammar WNT4 gene is present as a single copy in the genome of both males and females, indicating it is autosomal, as in other mammals (human: Chr 1 [8,39,40], mouse: Chr 4 and rat: Chr 5). WNT4 participates in multiple developmental events during embryogenesis, is broadly expressed in many adult tissues in mice and humans and has also been implicated in adult tissue homeostasis [1-3,7,41,42]. Semi-quantitative RT-PCR expression analyses in adult tammar tissues showed a similar pattern to that of human WNT4 consistent with a conserved and wide role for WNT4 in tissue homeostasis.

WNT4 also appears to be important for the normal pattern formation and development of both the male and female gonad [7]. In our study, using quantitative RT-PCR and immunohistochemistry, WNT4 was expressed at equal levels in the indifferent fetal and neonatal male and female gonads. At this time, protein in the ovary was localized to the somatic cells. Subsequently, WNT4 mRNA expression increased significantly to reach a peak at day 9–13, the time that ovarian cortex and medulla can be distinguished. After ovarian differentiation at day 12–13 postpartum, WNT4 expression remained localized in cortex and at the boundary of the cortex and medulla, but by day 45 pp, there was stronger expression in the medulla. The decreased WNT4 expression in the ovary to a level similar to that in testis, coincides with the time female germ cells enter meiosis [43].

In the testis, WNT4 gene expression was significantly down-regulated immediately after birth during the initial period of testicular differentiation, coinciding with the formation of seminiferous cords [13]. After cord formation, WNT4 levels increased slowly after day 8 postpartum and became specific to Leydig cells. By day 49, when secretion of testicular testosterone decreases (Fig. 5b) [32], Leydig cells stained strongly for WNT4. We suggest that once WNT4 reaches a critical threshold level, androgen production diminishes. The low level of immunostaining in the adult testis and ovary is consistent with their increase in steroidogenesis after puberty. This pattern of expression is therefore consistent with the hypothesis that WNT4 blocks initial testis differentiation, because the mRNA concentration is dramatically reduced and the WNT4 protein is localized to the tunica during this period of testicular development.

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