Kiss and Tell: Deletion of Kisspeptins and Receptors Reveal Surprising Results

Abstract

The well-known expression “Kiss and Tell” usually refers to revealing one’s sexual exploits or private matters. In the case of the transcription activator-like effector nucleases gene knockout studies by Tang et al (1), sequential removal of the 2 known kisspeptins and their receptors surprisingly reveals that this system is not required for reproduction. The authors rightly note that this challenges the idea that kisspeptin neurons are central regulators of vertebrate reproduction (eg, Refs. 2, 3 among many). To date, most observations leading to this conclusion are based on studies in mammals, including humans, rats, and mice, and thus may not reflect the diversity of neuroendocrine control mechanisms across the vertebrate groups. On the surface, this lack-of-effect study in zebrafish could be quite discouraging, except in the light of the evolution of neuropeptidergic systems controlling reproductive function. Zebrafish are members of a group of fish called teleosts. Teleosts are wonderfully diverse in their reproductive strategies, often beautiful, economically important, and there are nearly 30 000 species currently known (4). The evolutionof these ray-finned fishgoesbackapproximately 200 million years before present, after undergoing the third lineage-specific genome duplication (5). Complete or partial gene duplications in many teleosts have presented real challenges when trying to sort out the evolution and specific functions of reproductive neuropeptides. Many neuropeptides, neurotransmitter synthesis enzymes, and neurohormone receptors duplicated and/or mutated over time, resulting in an array of novel molecular substrates for the evolution of hormone systems. This may be one reason that teleosts are successful, being both widespread in distribution and fecund. These evolutionary duplication events in teleosts have generated multiple numbers of genes and peptides in comparison with their mammalian counterparts. For example, it has been observed that most fish species harbor 2 or 3 distinct GnRH genes and peptides (6, 7). Their location and functions are different, and early GnRH knockdown studies in trout revealed that reproduction may continue even with reduced GnRH levels (8). Subsequent studies revealed a more important role for the hypophysiotropic forms of GnRH in tilapia (9) and common carp (10). In both cases, reproduction was not inhibited in all animals expressing the GnRH antisense transgene. For the common carp, a close relative of zebrafish (family Cyprinidae, eg, carps, minnows, and goldfish), abnormal sexual development and infertility were observed in about 40% of the animals expressing the antisense transgene targeting the hypophysiotropic form of GnRH (10). On the other hand, the remaining 60% had normal gonads with sperm or eggs (10), indicating that reproduction was still possible in these carp. What about the kisspeptin knockout fish? Through rigorous analysis, the authors demonstrated that spermatogenesis, folliculogenesis, and reproductive capacity were not impaired in 6 mutant lines missing kisspeptins or kisspeptin receptors (1). It should be noted that thekisspeptin systemhasbeendescribed indetail in several fish, and there are significant differences between species, and in comparison with mammals. If one considers only zebrafish, Kah’s group (11), using specific antibodies, has clearly demonstrated that there are 2 independent kisspeptin systems (kiss1 and kiss2). The first is the habenular kiss1 system that is likely involved in nonreproductive activities, perhaps metabolic control. On the other hand, distribution of kiss2 neurons in hypophysiotropic areas