The Development of Kisspeptin Circuits in the Mammalian Brain - Kisspeptin Signaling in Reproductive Biology - page 216

originate during key stages of development. Sex differences are also seen in several
reproductive health disorders, such as idiopathic hypogonadotropic hypogonadism,
constitutional delayed puberty, and precocious puberty [ 1 - 5 ]. Many of these repro-
ductive health disorders have been attributed to known, or in many cases, unknown
developmental defects in the brain. Specifi c neuronal circuits located in the fore-
brain and hypothalamus have been implicated as control centers responsible for
proper development of reproductive physiology, converging on neurons that release
gonadotropin releasing hormone (GnRH). GnRH stimulates the release of luteiniz-
ing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary,
thereby driving the maturation and activation of the gonads. How and when the
developmental changes in the neuroendocrine axis are induced is not completely
known, but gaining a clearer understanding may help pinpoint the cause and timing
of defects in reproductive maturation.
One of the key upstream hypothalamic circuits involved in the control of GnRH
secretion consists of neurons expressing the Kiss1 gene and its protein product, kis-
speptin. Kisspeptin signaling has been implicated as an essential regulator of fertil-
ity and puberty in numerous mammalian species, including humans [ 6 - 8 ].
Alterations in the expression of Kiss1 or kisspeptin over development, along with
differences in expression between the sexes, especially during key developmental
periods, may be a critical driving force in the maturation of the neuroendocrine
reproductive system. Indeed, changes in the Kiss1 system likely contribute to the
timing of puberty onset, sex differences in LH secretion, and other facets of repro-
ductive physiology. It is therefore essential to understand how kisspeptin neurons
develop, when and how Kiss1 gene and protein expression are modifi ed during
development, and what possible regulatory mechanisms govern the development of
the kisspeptin system. This chapter discusses the current knowledge for these topics
in mammals and also pinpoints several important unanswered questions involving
the development of kisspeptin neuronal circuits.
Kiss1 and Kisspeptin Expression in the Adult Brain
In order to study the development of the kisspeptin system, it is essential to fi rst
understand the localization and phenotype of kisspeptin neurons in the adult state.
Until the recent generation of transgenic mice, which label kisspeptin cells with
markers such as GFP [ 9 - 11 ], three techniques were used to examine the localization
of kisspeptin neurons in the brain: reverse transcriptase PCR (RT-PCR)/quantitative
PCR (qPCR), in situ hybridization (ISH), and immunohistochemistry (IHC).
RT-PCR was used in early studies to identify high Kiss1 mRNA expression in large
regions of the brain, such as the hypothalamus [ 12 ]. However, this technique was
weakened by an inability to specifi cally visualize and separately analyze discrete
Kiss1 populations within these large brain areas. This issue was resolved through
the subsequent use of ISH and IHC, which allow for precise neuroanatomical map-
ping of Kiss1 - and kisspeptin-synthesizing neurons, respectively. However, in earlier