Neuropeptide Signaling: Unravelling the evolutionary history of kisspeptin

Experiments in sea cucumbers reveal how the physiological responses regulated by a neuropeptide called kisspeptin have evolved.
  1. Maria I Arnone  Is a corresponding author
  2. Paola Oliveri
  1. Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Italy
  2. Centre for Life’s Origins and Evolution, University College London, United Kingdom
  3. Research Department of Genetics, Evolution and Environment, University College London, United Kingdom

The world around us is constantly changing. As seasons shift, or as night turns to day, and food becomes more or less available, every organism must adapt their behavior and physiology to cope with its changing environment. The neuroendocrine systems play a central role in converting signals from the environment into biomolecules that can generate a response. Cells in these systems communicate by releasing various signals, including small proteins called neuropeptides. These molecules then travel towards their target cells where they bind to specific receptors and trigger a reaction that adjusts the physiology of cells and the tissues or organs they belong to (Tessmar-Raible, 2007).

A neuropeptide called kisspeptin is known to regulate fertility and reproduction in mammals (Hameed et al., 2011). The gene for kisspeptin is primarily expressed in the central nervous system, but is also active in other tissues such as the liver and heart. The gene that codes for its matching receptor shows a distinct but often overlapping pattern of expression (Bhattacharya and Babwah, 2015; Figure 1). Recent studies in adult mammals have revealed new physiological roles for this neuropeptide signaling system. For example, it has been shown that kisspeptin and its receptor regulate glucose homeostasis, feeding behavior and body mass composition by sending signals between the liver and pancreas (Wolfe and Hussain, 2018).

The role of kisspeptin in sea cucumbers and mammals.

Schematic showing the main organs that express kisspeptin (magenta) and/or its receptor (blue) in mammals (left panel) and sea cucumbers (right panel). The binding of kisspeptin (Kiss) to its receptor (KissR) triggers an intracellular pathway which sequentially activates the signaling molecules Ca2+/Gq/PLC/PKC/MAPK. This stimulates a molecule called ERK1/2 which regulates a number of cellular processes, including gene expression (center panel). Wang et al. showed that the signaling cascade triggered by kisspeptin regulates similar biological processes in mammals and sea cucumbers, such as reproduction, glucose metabolism and body mass.

Image credit: Maria I Arnone.

The genes for the neuropeptide kisspeptin and its receptor have also been identified in several marine invertebrates, including members of the echinoderm family, such as sea stars, sea urchins and sea cucumbers (Elphick et al., 2018). In sea urchins, it has been reported that the gene for kisspeptin is expressed in the gut of their larvae (Wood et al., 2018). However, we know relatively little about when and where this gene is expressed in other echinoderms or about its physiological role.

Now, in eLife, Naiming Zhou from Zhejiang University and co-workers – including Tianming Wang, Zheng Cao and Zhangfei Shen as joint first authors – report experiments identifying the location and role of the kisspeptin signaling system in the sea cucumber Apostichopus japonicus (Wang et al., 2020). This allowed the team (who are based in China and the US) to unravel the evolutionary history of this neuropeptide signaling system, which spans over more than 540 million years.

When studying the genome of A. japonicus, Wang et al. identified one gene which codes for two mature neuropeptides (AjKiss1a and AjKiss1b) and two genes which encode two receptor proteins (AjKissR1 and AjKissR2). In vitro experiments in cultured human cells showed that both neuropeptides are able to bind and specifically activate either receptor. Furthermore, the receptor proteins from sea cucumbers could also be activated by kisspeptin neuropeptides from other vertebrates, including humans.

Further experiments showed that when kisspeptin binds to either of the receptor proteins in human cells, this triggers an intracellular signaling pathway that eventually activates a molecule called MAPK (Castaño et al., 2009; Figure 1). These findings were further supported by in vivo experiments in the oocytes of sea cucumbers, in which the activation of MAPK was also detected following exposure to the neuropeptide AjKiss1b. This suggests that the molecular mechanisms activated by the kisspeptin signaling system are evolutionary conserved.

Next, Wang et al. studied the expression and physiological role of kisspeptin in adult sea cucumbers. This revealed that the precursor peptide for AjKiss1 is primarily expressed in the central nervous system (nerve ring) and gonads of A. japonicus, and its expression levels changed significantly during the reproductive season (Figure 1). The gene for the AjKiss1R1 receptor was also active in the nerve ring and gonads, in addition to other organs, including the muscles of the body-wall and respiratory tree that are only present in sea cucumbers (Spirina and Dolmatov, 2001).

When sea cucumbers were exposed to sustained high levels of the neuropeptide AjKiss1b, this upregulated the expression of proteins involved in the metabolism of glucose and induced a dormancy-like state known as aestivation: this is characterized by extensive weight loss and degeneration of the digestive tract. This suggests that, similar to vertebrates, the kisspeptin signaling system in sea cucumbers is also involved in regulating glucose metabolism, reproduction and body mass (Figure 1). The shared role of kisspeptin in vertebrates and sea cucumbers reveals important insights into how this neuropeptide signaling system evolved.

The findings of Wang et al. demonstrate how comparing the genomes and gene roles of different organisms can unravel new aspects of animal biology that may be useful for biomedical studies. Future studies on unexplored animals will shed further light on the complex interactions that allow organisms to adapt in response to their changing environment.

References

Article and author information

Author details

  1. Maria I Arnone

    Maria I Arnone is in the Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Naples, Italy

    For correspondence
    miarnone@szn.it
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9012-7624
  2. Paola Oliveri

    Paola Oliveri is in the Centre for Life’s Origins and Evolution, and the Research Department of Genetics, Evolution and Environment, University College London, London, United Kingdom

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3477-8529

Publication history

  1. Version of Record published:

Copyright

© 2020, Arnone and Oliveri

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 969
    views
  • 94
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Maria I Arnone
  2. Paola Oliveri
(2020)
Neuropeptide Signaling: Unravelling the evolutionary history of kisspeptin
eLife 9:e58599.
https://doi.org/10.7554/eLife.58599

Further reading

    1. Evolutionary Biology
    Thibaut Sellinger, Frank Johannes, Aurélien Tellier
    Research Article

    With the availability of high-quality full genome polymorphism (SNPs) data, it becomes feasible to study the past demographic and selective history of populations in exquisite detail. However, such inferences still suffer from a lack of statistical resolution for recent, for example bottlenecks, events, and/or for populations with small nucleotide diversity. Additional heritable (epi)genetic markers, such as indels, transposable elements, microsatellites, or cytosine methylation, may provide further, yet untapped, information on the recent past population history. We extend the Sequential Markovian Coalescent (SMC) framework to jointly use SNPs and other hyper-mutable markers. We are able to (1) improve the accuracy of demographic inference in recent times, (2) uncover past demographic events hidden to SNP-based inference methods, and (3) infer the hyper-mutable marker mutation rates under a finite site model. As a proof of principle, we focus on demographic inference in Arabidopsis thaliana using DNA methylation diversity data from 10 European natural accessions. We demonstrate that segregating single methylated polymorphisms (SMPs) satisfy the modeling assumptions of the SMC framework, while differentially methylated regions (DMRs) are not suitable as their length exceeds that of the genomic distance between two recombination events. Combining SNPs and SMPs while accounting for site- and region-level epimutation processes, we provide new estimates of the glacial age bottleneck and post-glacial population expansion of the European A. thaliana population. Our SMC framework readily accounts for a wide range of heritable genomic markers, thus paving the way for next-generation inference of evolutionary history by combining information from several genetic and epigenetic markers.

    1. Computational and Systems Biology
    2. Evolutionary Biology
    Kara Schmidlin, Sam Apodaca ... Kerry Geiler-Samerotte
    Research Article

    There is growing interest in designing multidrug therapies that leverage tradeoffs to combat resistance. Tradeoffs are common in evolution and occur when, for example, resistance to one drug results in sensitivity to another. Major questions remain about the extent to which tradeoffs are reliable, specifically, whether the mutants that provide resistance to a given drug all suffer similar tradeoffs. This question is difficult because the drug-resistant mutants observed in the clinic, and even those evolved in controlled laboratory settings, are often biased towards those that provide large fitness benefits. Thus, the mutations (and mechanisms) that provide drug resistance may be more diverse than current data suggests. Here, we perform evolution experiments utilizing lineage-tracking to capture a fuller spectrum of mutations that give yeast cells a fitness advantage in fluconazole, a common antifungal drug. We then quantify fitness tradeoffs for each of 774 evolved mutants across 12 environments, finding these mutants group into classes with characteristically different tradeoffs. Their unique tradeoffs may imply that each group of mutants affects fitness through different underlying mechanisms. Some of the groupings we find are surprising. For example, we find some mutants that resist single drugs do not resist their combination, while others do. And some mutants to the same gene have different tradeoffs than others. These findings, on one hand, demonstrate the difficulty in relying on consistent or intuitive tradeoffs when designing multidrug treatments. On the other hand, by demonstrating that hundreds of adaptive mutations can be reduced to a few groups with characteristic tradeoffs, our findings may yet empower multidrug strategies that leverage tradeoffs to combat resistance. More generally speaking, by grouping mutants that likely affect fitness through similar underlying mechanisms, our work guides efforts to map the phenotypic effects of mutation.