Gonadotropin-releasing hormone (GnRH) signaling regulates reproductive physiology in mammals. GnRH is released by a subset of hypothalamic neurons and binds to GnRH receptor (GnRHR) on gonadotropes in the anterior pituitary gland to control production and secretion of gonadotropins that in turn regulate the activity of the gonads. Central control of reproduction is well understood in adult animals, but GnRH signaling has also been implicated in the development of the reproductive axis. To investigate the role of GnRH signaling during development, we selectively ablated GnRHRexpressing cells in mice. This genetic strategy permitted us to identify an essential stage in male reproductive axis development, which depends on embryonic GnRH signaling. Our experiments revealed a striking dichotomy in the gonadotrope population of the fetal anterior pituitary gland. We show that luteinizing hormoneexpressing gonadotropes, but not follicle-stimulating hormoneexpressing gonadotropes, express the GnRHR at embryonic day 16.75. Furthermore, we demonstrate that an embryonic increase in luteinizing hormone secretion is needed to promote development of follicle-stimulating hormone-expressing gonadotropes, which might be mediated by paracrine interactions within the pituitary. Moreover, migration of GnRH neurons into the hypothalamus appeared normal with appropriate axonal connections to the median eminence, providing genetic evidence against autocrine regulation of GnRH neurons. Surprisingly, genetic ablation of GnRHR expressing cells significantly increased the number of GnRH neurons in the anterior hypothalamus, suggesting an unexpected role of GnRH signaling in establishing the size of the GnRH neuronal population. Our experiments define a functional role of embryonic GnRH signaling.gonadotropin-releasing hormone neurons | gonadotropin-releasing hormone receptor | gonadotrope development | diphtheria toxin | Cre recombinase R eproductive physiology in mammals is centrally regulated through the hypothalamic-pituitary-gonadal axis and depends on gonadotropin-releasing hormone (GnRH). GnRH signaling is well understood in adult animals, but has also been implicated in the development of the reproductive axis. The hormone is produced by a subset of neurons with a scattered distribution throughout the basal forebrain and released into the hypophyseal portal vasculature from axon terminals at the median eminence (1, 2). GnRH binds to the GnRH receptor (GnRHR), which is specifically expressed on gonadotrope cells in the anterior pituitary gland (3). GnRH signaling controls biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) that in turn regulate development and activity of the ovaries and testes (4).Studies in mice suggest that the hypothalamic-pituitarygonadal axis might already be functional during embryonic development. GnRH neurons have migrated from their place of origin in the nasal placodes to their final destination in the forebrain (5) and project neurosecretory axons to the median emi...
Hormone-secreting cells within the anterior pituitary gland may form organized and interdigitated networks that adapt to changing endocrine conditions in different physiological contexts. For gonadotropes, this might reflect a strategy to cope with acute changes throughout different female reproductive stages. The current study examined gonadotropes in female mice at characteristically different hormonal stages: prepubertal, postpubertal, and lactating. Gonadotrope plasticity was examined at the level of the whole population and single cells at different stages by imaging both fixed and live pituitary slices. The use of a model animal providing for the identification of selectively fluorescent gonadotropes allowed the particular advantage of defining cellular plasticity specifically for gonadotropes. In vivo analyses of gonadotropes relative to vasculature showed significantly different gonadotrope distributions across physiological states. Video microscopy studies using live slices ex vivo demonstrated pituitary cell plasticity in the form of movements and protrusions in response to GnRH. As positive feedback from rising estradiol levels is important for priming the anterior pituitary gland for the LH surge, experiments provide evidence of estradiol effects on GnRH signaling in gonadotropes. The experiments presented herein provide new insight into potential plasticity of gonadotropes within the anterior pituitary glands of female mice.
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