A widely employed germ cell marker is an ancient disordered protein with reproductive functions in diverse eukaryotes

  1. Michelle A Carmell  Is a corresponding author
  2. Gregoriy A Dokshin
  3. Helen Skaletsky
  4. Yueh-Chiang Hu
  5. Josien C von Wolfswinkel
  6. Kyomi J Igarashi
  7. Daniel W Bellott
  8. Michael Nefedov
  9. Peter W Reddien
  10. George C Enders
  11. Vladimir N Uversky
  12. Craig C Mello
  13. David C Page  Is a corresponding author
  1. Whitehead Institute, United States
  2. University of Massachusetts Medical School, United States
  3. Cincinnati Children's Hospital Medical Center, United States
  4. Yale University, United States
  5. University of Queensland, United States
  6. University of Kansas Medical Center, United States
  7. University of South Florida, United States

Abstract

The advent of sexual reproduction and the evolution of a dedicated germline in multicellular organisms are critical landmarks in eukaryotic evolution. We report an ancient family of GCNA (germ cell nuclear antigen) proteins that arose in the earliest eukaryotes, and feature a rapidly evolving intrinsically disordered region (IDR). Phylogenetic analysis reveals that GCNA proteins emerged before the major eukaryotic lineages diverged; GCNA predates the origin of a dedicated germline by a billion years. Gcna gene expression is enriched in reproductive cells across eukarya - either just prior to or during meiosis in single-celled eukaryotes, and in stem cells and germ cells of diverse multicellular animals. Studies of Gcna-mutant C. elegans and mice indicate that GCNA has functioned in reproduction for at least 600 million years. Homology to IDR-containing proteins implicated in DNA damage repair suggests that GCNA proteins may protect the genomic integrity of cells carrying a heritable genome.

Article and author information

Author details

  1. Michelle A Carmell

    Whitehead Institute, Cambridge, United States
    For correspondence
    carmell@wi.mit.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Gregoriy A Dokshin

    RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Helen Skaletsky

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yueh-Chiang Hu

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Josien C von Wolfswinkel

    Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kyomi J Igarashi

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniel W Bellott

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Michael Nefedov

    School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Peter W Reddien

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5569-333X
  10. George C Enders

    Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Vladimir N Uversky

    Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Craig C Mello

    RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. David C Page

    Whitehead Institute, Cambridge, United States
    For correspondence
    dcpage@wi.mit.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9920-3411

Funding

Howard Hughes Medical Institute

  • Michelle A Carmell
  • Gregoriy A Dokshin
  • Helen Skaletsky
  • Yueh-Chiang Hu
  • Kyomi J Igarashi
  • Daniel W Bellott
  • Peter W Reddien
  • Craig C Mello

Life Sciences Research Foundation

  • Michelle A Carmell

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse studies were performed using a protocol approved by the Committee on Animal Care at the Massachusetts Institute of Technology (Protocol number: 0714-074-17).

Copyright

© 2016, Carmell et al.

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

Metrics

  • 4,832
    views
  • 1,078
    downloads
  • 60
    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. Michelle A Carmell
  2. Gregoriy A Dokshin
  3. Helen Skaletsky
  4. Yueh-Chiang Hu
  5. Josien C von Wolfswinkel
  6. Kyomi J Igarashi
  7. Daniel W Bellott
  8. Michael Nefedov
  9. Peter W Reddien
  10. George C Enders
  11. Vladimir N Uversky
  12. Craig C Mello
  13. David C Page
(2016)
A widely employed germ cell marker is an ancient disordered protein with reproductive functions in diverse eukaryotes
eLife 5:e19993.
https://doi.org/10.7554/eLife.19993

Share this article

https://doi.org/10.7554/eLife.19993

Further reading

    1. Developmental Biology
    Michele Bertacchi, Gwendoline Maharaux ... Michèle Studer
    Research Article Updated

    The morphogen FGF8 establishes graded positional cues imparting regional cellular responses via modulation of early target genes. The roles of FGF signaling and its effector genes remain poorly characterized in human experimental models mimicking early fetal telencephalic development. We used hiPSC-derived cerebral organoids as an in vitro platform to investigate the effect of FGF8 signaling on neural identity and differentiation. We found that FGF8 treatment increases cellular heterogeneity, leading to distinct telencephalic and mesencephalic-like domains that co-develop in multi-regional organoids. Within telencephalic regions, FGF8 affects the anteroposterior and dorsoventral identity of neural progenitors and the balance between GABAergic and glutamatergic neurons, thus impacting spontaneous neuronal network activity. Moreover, FGF8 efficiently modulates key regulators responsible for several human neurodevelopmental disorders. Overall, our results show that FGF8 signaling is directly involved in both regional patterning and cellular diversity in human cerebral organoids and in modulating genes associated with normal and pathological neural development.

    1. Developmental Biology
    Shannon H Carroll, Sogand Schafer ... Eric C Liao
    Research Article

    Wnt signaling plays crucial roles in embryonic patterning including the regulation of convergent extension (CE) during gastrulation, the establishment of the dorsal axis, and later, craniofacial morphogenesis. Further, Wnt signaling is a crucial regulator of craniofacial morphogenesis. The adapter proteins Dact1 and Dact2 modulate the Wnt signaling pathway through binding to Disheveled. However, the distinct relative functions of Dact1 and Dact2 during embryogenesis remain unclear. We found that dact1 and dact2 genes have dynamic spatiotemporal expression domains that are reciprocal to one another suggesting distinct functions during zebrafish embryogenesis. Both dact1 and dact2 contribute to axis extension, with compound mutants exhibiting a similar CE defect and craniofacial phenotype to the wnt11f2 mutant. Utilizing single-cell RNAseq and an established noncanonical Wnt pathway mutant with a shortened axis (gpc4), we identified dact1/2-specific roles during early development. Comparative whole transcriptome analysis between wildtype and gpc4 and wildtype and dact1/2 compound mutants revealed a novel role for dact1/2 in regulating the mRNA expression of the classical calpain capn8. Overexpression of capn8 phenocopies dact1/2 craniofacial dysmorphology. These results identify a previously unappreciated role of capn8 and calcium-dependent proteolysis during embryogenesis. Taken together, our findings highlight the distinct and overlapping roles of dact1 and dact2 in embryonic craniofacial development, providing new insights into the multifaceted regulation of Wnt signaling.