They then extend their axons to the median eminence (ME) to allow secretion of GnRH into the hypophyseal portal system. From the OP, they migrate across the cribriform plate and through the basal forebrain to arrive within the presumptive hypothalamus by E17.5. GnRH neurons have a unique point of origin within the olfactory placode (OP) at embryonic day 11.5 (E11.5) ( Schwanzel-Fukuda and Pfaff, 1989 Wray et al., 1989 Schwanzel-Fukuda et al., 1992). GnRH stimulates the anterior pituitary gland to secrete gonadotropins, which, in turn, act on the gonads to control gametogenesis. Mammalian reproduction is mediated by the pulsatile release of gonadotropin-releasing hormone (GnRH) from a distinct population of neurons within the hypothalamus. Together, these data indicate that Si圆 plays an important role in the regulation of GnRH expression and hypothalamic control of fertility. Finally, we demonstrate that this induction in GnRH expression is mediated via binding of Si圆 to evolutionarily conserved ATTA sites located within the GnRH proximal promoter. We show that expression of Si圆 is dramatically increased during GnRH neuronal maturation and that overexpression of Si圆 induces GnRH transcription in neuronal cells. Although basal gonadotropin production in these mice is relatively normal, analysis of GnRH expression reveals a dramatic decrease in total GnRH neuron numbers. Female Si圆-null mice exhibit a striking decrease in fertility, failing to progress through the estrous cycle normally, show any signs of successful ovulation, or produce litters. In this study, we identify sine oculis-related homeobox 6 (Si圆) as a novel factor necessary for proper targeting of GnRH expression to the limited population of GnRH neurons within the adult mouse hypothalamus and demonstrate that it is required for proper reproductive function in both male and female mice. Control of the hypothalamic–pituitary–gonadal axis is dependent on correct migration of gonadotropin-releasing hormone (GnRH) neurons from the nasal placode to the hypothalamus, followed by proper synthesis and pulsatile secretion of GnRH, functions absent in patients with hypogonadal hypogonadism. The hypothalamus, pituitary, and gonads coordinate to direct the development and regulation of reproductive function in mammals.
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