In mammals, sex is determined when the undifferentiated and bipotential embryonic gonad, otherwise known as the genital ridge, becomes either a testis or an ovary. The molecular mechanisms of mammalian sex determination are poorly understood as known genetic defects have been identified in only a minority of sex-reversed patients (XX males, XY females, XX true hermaphrodites). Until recently, only transcription factors such as SRY, SOX9, DAX1, WT1 and SF1 were known to be involved in this process. We and others showed that WNT-4 is a new sex-determining signaling molecule responsible for masculinization of XX mouse pups when deleted, and for XY sex reversal when duplicated and overexpressed in humans. Our goal is to assess the influence of Wnt-4 dosage on mammalian sexual development using a transgenic animal model (Specific Aim 1), and to characterize the molecular mechanisms of Wnt-4 action in the sex determination pathway using a Sertoli cell line system (Specific Aim 2). We will test the hypothesis that mammalian sex determination is sensitive to gene dosage by assessing the effect of various doses of WNT- 4 on sexual development of transgenic mice. We will also test the validity of a proposed model for sex determination by identifying the physiological target of Wnt-4 and by characterizing the mechanisms of control of Wnt-4 expression and signaling. Finally, we have shown that WNT-4 disrupts the vascular development of XY gonads. Since there are divergent angiogenic mechanisms between XX and XY gonads that establish the distinct arterial systems in developing testes and ovaries, we will test how WNT-4 influences the sex-specific vascularization of the gonads (Specific Aim 3). Dissecting the molecular pathway of mammalian sex determination will be crucial in understanding the development of the gonads, and the pathophysiology of human disorders of sexual development.
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