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

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

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

  • 36,870
    views
  • 2,176
    downloads
  • 98
    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. Sebastian Ocklenburg
  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
(2017)
Epigenetic regulation of lateralized fetal spinal gene expression underlies hemispheric asymmetries
eLife 6:e22784.
https://doi.org/10.7554/eLife.22784

Share this article

https://doi.org/10.7554/eLife.22784

Further reading

    1. Neuroscience
    Gyeong Hee Pyeon, Hyewon Cho ... Yong Sang Jo
    Research Article Updated

    Recent studies suggest that calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) represent aversive information and signal a general alarm to the forebrain. If CGRP neurons serve as a true general alarm, their activation would modulate both passive nad active defensive behaviors depending on the magnitude and context of the threat. However, most prior research has focused on the role of CGRP neurons in passive freezing responses, with limited exploration of their involvement in active defensive behaviors. To address this, we examined the role of CGRP neurons in active defensive behavior using a predator-like robot programmed to chase mice. Our electrophysiological results revealed that CGRP neurons encode the intensity of aversive stimuli through variations in firing durations and amplitudes. Optogenetic activation of CGRP neurons during robot chasing elevated flight responses in both conditioning and retention tests, presumably by amplifying the perception of the threat as more imminent and dangerous. In contrast, animals with inactivated CGRP neurons exhibited reduced flight responses, even when the robot was programmed to appear highly threatening during conditioning. These findings expand the understanding of CGRP neurons in the PBN as a critical alarm system, capable of dynamically regulating active defensive behaviors by amplifying threat perception, and ensuring adaptive responses to varying levels of danger.

    1. Neuroscience
    Alessandro Piccin, Anne-Emilie Allain ... Angelo Contarino
    Research Article

    Substance-induced social behavior deficits dramatically worsen the clinical outcome of substance use disorders; yet, the underlying mechanisms remain poorly understood. Herein, we investigated the role for the corticotropin-releasing factor receptor 1 (CRF1) in the acute sociability deficits induced by morphine and the related activity of oxytocin (OXY)- and arginine-vasopressin (AVP)-expressing neurons of the paraventricular nucleus of the hypothalamus (PVN). For this purpose, we used both the CRF1 receptor-preferring antagonist compound antalarmin and the genetic mouse model of CRF1 receptor-deficiency. Antalarmin completely abolished sociability deficits induced by morphine in male, but not in female, C57BL/6J mice. Accordingly, genetic CRF1 receptor-deficiency eliminated morphine-induced sociability deficits in male mice. Ex vivo electrophysiology studies showed that antalarmin also eliminated morphine-induced firing of PVN neurons in male, but not in female, C57BL/6J mice. Likewise, genetic CRF1 receptor-deficiency reduced morphine-induced firing of PVN neurons in a CRF1 gene expression-dependent manner. The electrophysiology results consistently mirrored the behavioral results, indicating a link between morphine-induced PVN activity and sociability deficits. Interestingly, in male mice antalarmin abolished morphine-induced firing in neurons co-expressing OXY and AVP, but not in neurons expressing only AVP. In contrast, in female mice antalarmin did not affect morphine-induced firing of neurons co-expressing OXY and AVP or only OXY, indicating a selective sex-specific role for the CRF1 receptor in opiate-induced PVN OXY activity. The present findings demonstrate a major, sex-linked, role for the CRF1 receptor in sociability deficits and related brain alterations induced by morphine, suggesting new therapeutic strategy for opiate use disorders.