Abstract
Kisspeptin1 (product of the Kiss1 gene) is the key neuropeptide that gates puberty and maintains fertility by regulating the gonadotropin-releasing hormone (GnRH) neuronal system in mammals. Inactivating mutations in Kiss1 and the kisspeptin receptor (GPR54/Kiss1r) are associated with pubertal failure and infertility. Kiss2, a paralogous gene for kiss1, has been recently identified in several vertebrates including zebrafish. Using our transgenic zebrafish model system in which the GnRH3 promoter drives expression of emerald green fluorescent protein, we investigated the effects of kisspeptins on development of the GnRH neuronal system during embryogenesis and on electrical activity during adulthood. Quantitative PCR showed detectable levels of kiss1 and kiss2 mRNA by 1 day post fertilization, increasing throughout embryonic and larval development. Early treatment with Kiss1 or Kiss2 showed that both kisspeptins stimulated proliferation of trigeminal GnRH3 neurons located in the peripheral nervous system. However, only Kiss1, but not Kiss2, stimulated proliferation of terminal nerve and hypothalamic populations of GnRH3 neurons in the central nervous system. Immunohistochemical analysis of synaptic vesicle protein 2 suggested that Kiss1, but not Kiss2, increased synaptic contacts on the cell body and along the terminal nerve-GnRH3 neuronal processes during embryogenesis. In intact brain of adult zebrafish, whole-cell patch clamp recordings of GnRH3 neurons from the preoptic area and hypothalamus revealed opposite effects of Kiss1 and Kiss2 on spontaneous action potential firing frequency and membrane potential. Kiss1 increased spike frequency and depolarized membrane potential, whereas Kiss2 suppressed spike frequency and hyperpolarized membrane potential. We conclude that in zebrafish, Kiss1 is the primary stimulator of GnRH3 neuronal development in the embryo and an activator of stimulating hypophysiotropic neuron activities in the adult, while Kiss2 plays an additional role in stimulating embryonic development of the trigeminal neuronal population, but is an RFamide that inhibits electrical activity of hypophysiotropic GnRH3 neurons in the adult.
Highlights
KISS1 and its receptor play major roles controlling the reproductive system in vertebrates [1,2,3,4,5]
Given that zebrafish kiss1 and kiss2 mRNAs are expressed during embryonic and larval development [16], we explored the relative actions of Kiss1 and Kiss2 on morphological development of multiple populations of GnRH3 neurons during embryogenesis
Both kiss1 and kiss2 mRNAs were detectable at 1 dpf and increased during the first week of life, similar to the results reported by Kitahashi and colleagues (2009) [16]
Summary
KISS1 and its receptor play major roles controlling the reproductive system in vertebrates [1,2,3,4,5]. The Kiss1r is expressed widely in the brain, including on GnRH1 neurons that form the final common pathway regulating the pituitary-gonadal axis [9,10,11]. Studies in adult zebrafish showed that Kiss neurons are located in the habenula, while Kiss neurons are located in the posterior tuberal nucleus and the dorsal and ventral hypothalamus [18,19]. The ventral forebrain (including POA and hypothalamus) is rich in GnRH3 neurons that regulate reproduction in zebrafish, and it was found that Kiss neural processes were in close apposition to GnRH3 neurons in this region [18]. The localization of Kiss and Kiss 2 neurons suggests that in adult zebrafish, Kiss neurons are the primary regulators of the brainpituitary-gonadal axis, while Kiss neurons serve other functions (such as regulating the serotonergic system) [19,20]
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