Circadian Regulation of Kisspeptin in Female Reproductive Functioning - Kisspeptin Signaling in Reproductive Biology - page 375

increased spontaneous abortion rate [ 2 ], suggesting the importance of circadian
functioning in ovulation and pregnancy maintenance. Likewise, the luteinizing hor-
mone (LH) surge that initiates ovulation occurs in early morning in women [ 3 ] and
diurnal rodents [ 4 ], but in early evening in nocturnal rodents (reviewed in [ 5 ]). In
rodents, disruptions of the master circadian clock in the brain, its neural output, or
the genes regulating cellular clock function lead to pronounced abnormalities in
ovulation and fecundity [ 6 - 8 ]. Given the necessity of proper hormonal timing in
female reproductive health, and the experimental tractability of the reproductive
axis, the study of female reproductive functioning represents an ideal model system
for understanding circadian endocrine control. As is apparent throughout this topic,
kisspeptin is essential for reproductive functioning and, not surprisingly, represents
a critical node in the network of circadian regulation underlying female reproduc-
tive health. The present chapter provides a broad overview of circadian control of
female reproduction, underscoring the signifi cance of kisspeptin signaling within
this framework.
The Circadian Timing System
Four decades ago, two studies provided strong evidence that the suprachiasmatic
nucleus (SCN) of the hypothalamus was the locus of the master circadian pace-
maker in mammals [ 9 , 10 ]. In these initial studies, electrolytic lesions of the SCN
abolished rhythms in locomotor and drinking behavior and adrenal glucocorticoids,
suggesting that either the circadian clock is localized to the SCN, that the SCN is
part of a larger network responsible for circadian rhythm generation, or that fi bers
of passage required for circadian functioning traveled through this neural locus.
Numerous converging lines of evidence since these initial investigations, from a
host of laboratories, have confi rmed the role of the SCN as a master pacemaker. For
example, transplants of donor SCN tissue into the brains of arrhythmic, SCN-
lesioned hosts restore circadian rhythmicity in behavior [ 11 , 12 ]. Importantly,
rhythms are restored with the period of the donor SCN, indicating that the trans-
planted tissue does not act by restoring host-brain function but that the “clock” is
contained in the transplanted tissue. Furthermore, circadian rhythms in neural fi ring
rate persist in isolated SCN tissue maintained in culture [ 13 ], demonstrating that
input from extra-SCN brain sites is not necessary for circadian rhythm generation.
Although circadian rhythms are endogenously generated, in order to be adaptive for
an organism, these rhythms must be synchronized to the external environment. This
entrainment is accomplished via direct neural projections from intrinsically photo-
sensitive retinal ganglion cells to the circadian clock in the SCN [ 14 - 19 ].
At the cellular level, circadian rhythms are generated by 24-h autoregulatory
transcriptional/translational feedback loops consisting of “clock” genes and their
protein products (Fig. 18.1 ) [ 20 - 23 ]. In mammals, the feedback loop begins in the
cell nucleus where CLOCK and BMAL1 proteins heterodimerize and drive the tran-
scription of the Period ( Per1 and Per2 ) and Cryptochrome ( Cry1 and Cry2 ) genes