Three distinct hedgehog (HH) molecules, (sonic, desert, and indian), two HH receptors (PTCH1 and PTCH2), a membrane bound activator (SMO), and downstream three transcription factors (GLI1, GLI2, and GLI3) are the major components of the HH signaling. These signaling molecules were initially identified in Drosophila melanogaster. Later, it has been found that the HH system is highly conserved across species and essential for organogenesis. HH signaling pathways play key roles in the development of the brain, face, skeleton, musculature, lungs, and gastrointestinal tract. While the sonic HH (SHH) pathway plays a major role in the development of the central nervous system, the desert HH (DHH) regulates the development of the gonads, and the indian HH (IHH) acts on the development of bones and joints. There are also overlapping roles among the HH molecules. In addition to the developmental role of HH signaling in embryonic life, the pathways possess vital physiological roles in testes and ovaries during adult life. Disruption of DHH and/or IHH signaling results in ineffective gonadal steroidogenesis and gametogenesis. While DHH regulates the male gonadal functions, ovarian functions are regulated by both DHH and IHH. This review article focuses on the roles of HH signaling in gonadal development and reproductive functions with an emphasis on ovarian functions. We have acknowledged the original research work that initially reported the findings and discussed the subsequent studies that have further analyzed the role of HH signaling in testes and ovaries.

Kisspeptin (KP) and kisspeptin receptor (KPR) are essential for the onset of puberty, development of gonads, and maintenance of gonadal function in both males and females. Hypothalamic KPs and KPR display a high degree of sexual dimorphism in expression and function. KPs act on KPR in gonadotropin releasing hormone (GnRH) neurons and induce distinct patterns of GnRH secretion in males and females. GnRH acts on the anterior pituitary to secrete gonadotropins, which are required for steroidogenesis and gametogenesis in testes and ovaries. Gonadal steroid hormones in turn regulate the KP neurons. Gonadal hormones inhibit the KP neurons within the arcuate nucleus and generate pulsatile GnRH mediated gonadotropin (GPN) secretion in both sexes. However, the numbers of KP neurons in the anteroventral periventricular nucleus and preoptic area are greater in females, which release a large amount of KPs in response to a high estrogen level and induce the preovulatory GPN surge. In addition to the hypothalamus, KPs and KPR are also expressed in various extrahypothalamic tissues including the liver, pancreas, fat, and gonads. There is a remarkable difference in circulating KP levels between males and females. An increased level of KPs in females can be linked to increased numbers of KP neurons in female hypothalamus and more KP production in the ovaries and adipose tissues. Although the sexually dimorphic features are well characterized for hypothalamic KPs, very little is known about the extrahypothalamic KPs. This review article summarizes current knowledge regarding the sexual dimorphism in hypothalamic as well as extrahypothalamic KP and KPR system in primates and rodents.

Increased activation of ovarian primordial follicles in Erβ knockout (Erβ^KO) rats becomes evident as early as postnatal day 8.5. To identify the ERβ-regulated genes that may control ovarian primordial follicle activation, we analyzed the transcriptome profiles of Erβ^KO rat ovaries collected on postnatal days 4.5, 6.5, and 8.5. Compared to wildtype ovaries, Erβ^KO ovaries displayed dramatic downregulation of Indian hedgehog (Ihh) expression. IHH-regulated genes, including Hhip, Gli1, and Ptch1, were also downregulated in Erβ^KO ovaries. This was associated with a downregulation of steroidogenic enzymes Cyp11a1, Cyp19a1, and Hsd17b1. The expression of Ihh remained very low in Erβ^KO ovaries despite the high levels of Gdf9 and Bmp15, which are known upregulators of Ihh expression in the granulosa cells of activated ovarian follicles. Strikingly, the downregulation of the Ihh gene in Erβ^KO ovaries began to disappear on postnatal day 16.5 and recovered on postnatal day 21.5. In rat ovaries, the first wave of primordial follicles is rapidly activated after their formation, whereas the second wave of primordial follicles remains dormant in the ovarian cortex and slowly starts activating after postnatal day 12.5. We localized the expression of Ihh mRNA in postnatal day 8.5 wildtype rat ovaries but not in the age-matched Erβ^KO ovaries. In postnatal day 21.5 Erβ^KO rat ovaries, we detected Ihh mRNA mainly in the activated follicles in the ovaries’ peripheral regions. Our findings indicate that the expression of Ihh in the granulosa cells of the activated first wave of ovarian follicles depends on ERβ.