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• Kisspeptin-GPR54 in the Female Neuroendocrine Axis
• Brain Genes Governing Reproduction
• KiSS-1 Signaling and Regulation in the Male Mouse
Kisspeptin-GPR54 in the Female Neuroendocrine Axis
Robert A Steiner, PhD
The KiSS-1 gene codes for kisspeptins, which bind to a G protein-coupled receptor known as GPR54. KiSS-1 and GPR54 are expressed in the forebrain, and mutations in the GPR54 gene cause hypo-gonadotropic hypogonadism in humans and mice. Kisspeptins stimulate gonadotropin-releasing hormone (GnRH) and gonadotropin (LH and FSH) secretion, and the KiSS-1 gene is regulated by gonadal steroids, suggesting that signaling through GPR54 plays a critical role in the neuroendocrine regulation of reproduction. In the male mouse, KiSS-1 neurons in the arcuate nucleus (Arc) and anteroventral periventricular nucleus (AVPV) are differentially regulated by testosterone (T), which inhibits KiSS-1 expression in the Arc and stiumlates its expression in the AVPV; these actions are mediated through both androgen and estrogen alpha receptors.
Primary Objectives
1) To determine the physiological significance of kisspeptin-GPR54 signaling the Arc.
In this context, we will :
- Test the hypothesis that KiSS-1 neurons in the Arc play an important role in mediating the negative feedback effect of T on gonadotropin secretion
- Determine whether kisspeptin-GPR54 signaling is involved in mediating the neuroendocrine effects of metabolic signals
2) To investigate the differences in the physiological function and network organization
between KiSS-1 neurons in the AVPV and those in the Arc. Here we will:
- Evaluate the physiological impact of genetically deleting KiSS-1 gene expression specifically in the AVPV (but not in the Arc)
- Develop a transgenic mouse that expresses GFP in KiSS-1 neurons and investigate the electro-physiological properties of KiSS-1 neurons in the AVPV and Arc
- Use double-labeling techniques for in situ hybridization and immunocytochemistry to determine the unique molecular profile and circuitry of KiSS-1 neurons in these two regions
Elucidating the functional significance, regulation and mechanism of kisspeptin’s action in the brain may advance our understanding of idiopathic hypogonadotropic hypogonadism and other neuro-endocrine disorders and could provide the scientific rationale for improved therapies to treat precocious or delayed puberty and infertility. It is also conceivable that this knowledge could serve as the basis for the development of new and better strategies for hormonal contraception in men.
Funding Source: NIH
Contact: Robert A Steiner, PhD, (206) 543-8712
Ends 4/30/11
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Brain Genes Governing Reproduction
Galanin-like peptide (GALP) is a newly discovered member of the galanin family of neuropeptides. GALP shares a partial sequence homology with galanin; however, GALP is coded by a separate gene and is likely to have its own unique receptor.
Work from our laboratory and others has shown that the expression of GALP mRNA in the brain is limited to a cluster of neurons in the hypothalamic arcuate nucleus and the median eminence. We have recently discovered that GALP neurons are direct targets for the adipocyte-derived hormone leptin. The expression of GALP mRNA is reduced in leptin-deficient states, which can be reversed by the concomitant administration of leptin. When administered into the brain, GALP produces a dose-dependent inhibition of feeding and body weight and also stimulates luteininzing hormone (LH) and testosterone secretion.
These studies suggest that GALP neurons serve as part of the hypothalamic circuitry linking the regulation of body weight and reproduction; however, beyond these observations, we understand little about GALP's physiological importance. We propose to use neuroanatomical, pharmacological, and molecular biological techniques to reveal the anatomical circuitry governing GALP cells, map their projections, and discern GALP's functional significance. Learning the basic circuitry that couples GALP to other neuronal systems, understanding more about the molecular physiology of GALP neurons, establishing the cellular, molecular, and physiological effects of GALP, and learning how GALP neurons are regulated by metabolic hormones are fundamental to understanding GALP's functional role in the orchestration of the neuroendocrine reproductive system, as well as other important physiological processes.
Funding Source: NIH
Contact: Robert A Steiner, PhD, (206) 543-8712
Ends 4/30/11
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KiSS-1 Signaling and Regulation in the Male Mouse
Robert A Steiner, PhD
The KiSS-1 gene codes for kisspeptins, which have been implicated in the neuroendocrine regulation of reproduction. In the brain, KiSS-1 mRNA-expressing neurons are located in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei. KiSS-1 neurons in the AVPV appear to play a role in generating the preovulatory GnRH/LH surge, which occurs only in females and is organized peri-natally by gonadal steroids.
Because KiSS-1 is involved in the sexually dimorphic GnRH/LH surge, we hypothesized that KiSS-1 expression is sexually differentiated, with females having more KiSS-1 neurons than either males or neonatally androgenized females. To test this, male and female rats were neonatally treated with androgen or vehicle; then, as adults, they were left intact or gonadectomized and implanted with capsules containing sex steroids or nothing. KiSS-1 mRNA levels in the AVPV and ARC were determined by in situ hybridization. Normal females expressed significantly more KiSS-1 mRNA in the AVPV than normal males, even under identical adult hormonal conditions. This KiSS-1 sex difference was organized perinatally, as demonstrated by the observation that neonatally androgenized females displayed a male-like pattern of adulthood KiSS-1 expression in the AVPV.
In contrast, there was neither a sex difference nor an influence of neonatal treatment in KiSS-1 expression in the ARC. Using double-labeling techniques, we determined that the sexually differentiated KiSS-1 neurons in the AVPV are distinct from the sexually differentiated population of tyrosine hydroxylase (dopaminergic) neurons in this region. Our findings suggest that sex differences in kisspeptin signaling from the AVPV subserve the cellular mechanisms controlling the sexually differentiated GnRH/LH surge.
Funding Source: NIH
Contact: Robert A Steiner, PhD, (206) 543-8712
Ends 3/31/11
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