1. Neuroscience
Download icon

Epigenetic regulation of lateralized fetal spinal gene expression underlies hemispheric asymmetries

  1. Sebastian Ocklenburg  Is a corresponding author
  2. Judith Schmitz
  3. Zahra Moinfar
  4. Dirk Moser
  5. Rena Klose
  6. Stephanie Lor
  7. Georg Kunz
  8. Martin Tegenthoff
  9. Pedro M Faustmann
  10. Clyde Francks
  11. Jörg T Epplen
  12. Robert Kumsta
  13. Onur Güntürkün
  1. Ruhr University Bochum, Germany
  2. St. Johannes Hospital, Germany
  3. University Hospital Bergmannsheil, Germany
  4. Max Planck Institute for Psycholinguistics, Netherlands
Research Article
  • Cited 41
  • Views 31,406
  • Annotations
Cite this article as: eLife 2017;6:e22784 doi: 10.7554/eLife.22784

Abstract

Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-β signaling pathway and lateralized methylation of CpG islands. Our findings suggest molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans.

Article and author information

Author details

  1. Sebastian Ocklenburg

    Department of Biopsychology, Institute of Cognitive Neuroscience, Ruhr University Bochum, Bochum, Germany
    For correspondence
    sebastian.ocklenburg@rub.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5882-3200
  2. Judith Schmitz

    Department of Biopsychology, Institute of Cognitive Neuroscience, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Zahra Moinfar

    Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Dirk Moser

    Department of Genetic Psychology, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Rena Klose

    Department of Biopsychology, Institute of Cognitive Neuroscience, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Stephanie Lor

    Department of Biopsychology, Institute of Cognitive Neuroscience, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Georg Kunz

    Department of Obstetrics and Gynecology, St. Johannes Hospital, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Martin Tegenthoff

    Department of Neurology, University Hospital Bergmannsheil, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Pedro M Faustmann

    Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Clyde Francks

    Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Jörg T Epplen

    Department of Human Genetics, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Robert Kumsta

    Department of Genetic Psychology, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Onur Güntürkün

    Department of Biopsychology, Institute of Cognitive Neuroscience, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.

Funding

Deutsche Forschungsgemeinschaft (Gu227/16-1)

  • Onur Güntürkün

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

Ethics

Human subjects: The study was approved by the Ethics Committee of the Medical Faculty of the Ruhr-University Bochum (registration number 5056-14). All fetal tissue donors signed written informed consent

Reviewing Editor

  1. Heidi Johansen-Berg, University of Oxford, United Kingdom

Publication history

  1. Received: October 29, 2016
  2. Accepted: January 31, 2017
  3. Accepted Manuscript published: February 1, 2017 (version 1)
  4. Version of Record published: February 7, 2017 (version 2)

Copyright

© 2017, Ocklenburg 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

  • 31,406
    Page views
  • 1,890
    Downloads
  • 41
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

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)

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

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

Further reading

    1. Neuroscience
    Gabriela Manzano Nieves et al.
    Research Article Updated

    Early life adversity (ELA) is associated with increased risk for stress-related disorders later in life. The link between ELA and risk for psychopathology is well established but the developmental mechanisms remain unclear. Using a mouse model of resource insecurity, limited bedding (LB), we tested the effects of LB on the development of fear learning and neuronal structures involved in emotional regulation, the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). LB delayed the ability of peri-weanling (21 days old) mice to express, but not form, an auditory conditioned fear memory. LB accelerated the developmental emergence of parvalbumin (PV)-positive cells in the BLA and increased anatomical connections between PL and BLA. Fear expression in LB mice was rescued through optogenetic inactivation of PV-positive cells in the BLA. The current results provide a model of transiently blunted emotional reactivity in early development, with latent fear-associated memories emerging later in adolescence.

    1. Neuroscience
    Víctor J López-Madrona et al.
    Research Article Updated

    Hippocampal firing is organized in theta sequences controlled by internal memory processes and by external sensory cues, but how these computations are coordinated is not fully understood. Although theta activity is commonly studied as a unique coherent oscillation, it is the result of complex interactions between different rhythm generators. Here, by separating hippocampal theta activity in three different current generators, we found epochs with variable theta frequency and phase coupling, suggesting flexible interactions between theta generators. We found that epochs of highly synchronized theta rhythmicity preferentially occurred during behavioral tasks requiring coordination between internal memory representations and incoming sensory information. In addition, we found that gamma oscillations were associated with specific theta generators and the strength of theta-gamma coupling predicted the synchronization between theta generators. We propose a mechanism for segregating or integrating hippocampal computations based on the flexible coordination of different theta frameworks to accommodate the cognitive needs.