Kisspeptin: Past, Present, and Prologue - Kisspeptin Signaling in Reproductive Biology - page 5

in adulthood and development. There are many cellular “phenotypes” of kisspeptin
neurons, whose anatomy and physiology varies among species and as a function of
age and sex. Some kisspeptin neurons coexpress neurokinin B (NKB) and dynorphin
(at the very least!), whereas others express a completely different array of co-transmitters
(such as tyrosine hydroxylase). Sex steroids, including estradiol and testosterone,
act through the estradiol receptor and the androgen receptor to regulate the expres-

sion of Kiss1 in kisspeptin neurons. Moreover, the effect of these sex steroids
depend on the particular phenotype of their target cells, as well as the age and sex
of the animal. Metabolic hormones, such as leptin, act directly (and indirectly) on
kisspeptin neurons to regulate their function, and may play a role in inhibiting
reproduction during lactation and stress [ 5 ]. We also suspect that the Kiss1 gene is
subject to developmental regulation—perhaps through epigenetic mechanisms,
which become manifest in adulthood.
Notwithstanding these accomplishments, controversies remain. Debate surrounds
the precise role of certain anatomical subsets of kisspeptin neurons in regulating
gonadotropin secretion. Which population of kisspeptin controls the onset of
puberty ? Which mediates the negative and positive feedback effects of estradiol on
GnRH secretion ? Do metabolic hormones exert direct or indirect effects on kiss-
peptin neurons ? Are kisspeptin neurons “ responsible ” for driving pulsatile GnRH
( and LH ) secretion ? How does the functional anatomy of different populations of
kisspeptin neurons differ among species ? Controversy also attends the nature and
interpretation of studies in transgenic animal models expressing GFP and/or Cre
recombinase (Cre) under the Kiss1 promoter and the phenotype of animals gener-
ated by crossing the Cre mice with fl oxed alleles. Such studies are complicated by
the promiscuous nature of Cre expression in Kiss1 transgenic crosses with reporters
and in Kiss1 knock-in mice, wherein the stochastic properties of Cre expression
may (or may not) produce offspring with the expected results of targeted manipula-
tion [ 6 , 7 ]. This all translates into confusion about (1) interpreting electrophysiolog-
ical results predicated on identifying kisspeptin neurons in slice preparations based
on the presence of GFP—produced by crossing Kiss1 - Cre mice with transgenic
mice reporters (GFP) and (2) creating cell-specifi c knockouts of genes that are
coexpressed in kisspeptin neurons by crossing Kiss1 - Cre lines with fl oxed alleles.
So, what does the future hold ? What remains to be learned about kisspeptin sig-
naling ? Certainly, we can dissect more about the details of kisspeptin's molecular
action on GnRH neurons—worthy, perhaps, but may fi nd rough sledding in funding
agencies. We can (and certainly will) explore the diversity of kisspeptin's action in
regions of the brain outside of the hypothalamus (e.g., hippocampus, cortex, amyg-
dala)—also worthwhile, but outside of the context of a physiological problem, such
ventures may be viewed as molecular bird-watching. It is essential that we learn
more about kisspeptin signaling in the brain of species besides rodents, including
humans, to learn more about how kisspeptin neurons are regulated in creatures like
us and what it means for puberty and menstrual cycle function. Understanding the
role of kisspeptin neurons in the generation of pulsatile GnRH secretion remains
one of neuroendocrinology's most fundamental problems—a keystone. Parsing the
signifi cance of kisspeptin's co-transmitters in the arcuate nucleus (i.e., NKB and

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