Homeodomain protein Otp affects developmental neuropeptide switching in oxytocin neurons associated with a long-term effect on social behavior

  1. Einav Wircer
  2. Janna Blechman
  3. Nataliya Borodovsky
  4. Michael Tsoory
  5. Ana Rita Nunes
  6. Rui F Oliveira
  7. Gil Levkowitz  Is a corresponding author
  1. Weizmann Institute of Science, Israel
  2. Instituto Gulbenkian de Ciência, Portugal

Abstract

Proper response to stress and social stimuli depends on orchestrated development of hypothalamic neuronal circuits. Here we address the effects of the developmental transcription factor orthopedia (Otp) on hypothalamic development and function. We show that developmental mutations in the zebrafish paralogous gene otpa but not otpb affect both stress response and social preference. These behavioral phenotypes were associated with developmental alterations in oxytocinergic (OXT) neurons. Thus, otpa and otpb differentially regulate neuropeptide switching in a newly identified subset of OXT neurons that co-express the corticotropin-releasing hormone (CRH). Single-cell analysis revealed that these neurons project mostly to the hindbrain and spinal cord. Ablation of this neuronal subset specifically reduced adult social preference without affecting stress behavior, thereby uncoupling the contribution of a specific OXT cluster to social behavior from the general otpa-/- deficits. Our findings reveal a new role for Otp in controlling developmental neuropeptide balance in a discrete OXT circuit whose disrupted development affects social behavior.

Article and author information

Author details

  1. Einav Wircer

    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Janna Blechman

    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Nataliya Borodovsky

    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael Tsoory

    Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Ana Rita Nunes

    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Rui F Oliveira

    Integrative Behavioural Biology Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1528-618X
  7. Gil Levkowitz

    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
    For correspondence
    gil.levkowitz@weizmann.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3896-1881

Funding

Israel Science Foundation (1511/16)

  • Einav Wircer
  • Janna Blechman
  • Gil Levkowitz

Israel Science Foundation (957/12)

  • Einav Wircer
  • Janna Blechman
  • Nataliya Borodovsky
  • Gil Levkowitz

Israel Science Foundation (2137/16)

  • Janna Blechman
  • Gil Levkowitz

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 procedures were approved by the Weizmann Institute's Institutional Animal Care and Use Committee protocol (27220516-3)

Reviewing Editor

  1. Joel K Elmquist, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: October 7, 2016
  2. Accepted: January 16, 2017
  3. Accepted Manuscript published: January 17, 2017 (version 1)
  4. Version of Record published: February 6, 2017 (version 2)

Copyright

© 2017, Wircer 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

  • 2,725
    Page views
  • 520
    Downloads
  • 29
    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)

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. Einav Wircer
  2. Janna Blechman
  3. Nataliya Borodovsky
  4. Michael Tsoory
  5. Ana Rita Nunes
  6. Rui F Oliveira
  7. Gil Levkowitz
(2017)
Homeodomain protein Otp affects developmental neuropeptide switching in oxytocin neurons associated with a long-term effect on social behavior
eLife 6:e22170.
https://doi.org/10.7554/eLife.22170

Further reading

    1. Developmental Biology
    2. Evolutionary Biology
    Alexandre P Thiery et al.
    Research Article Updated

    Development of tooth shape is regulated by the enamel knot signalling centre, at least in mammals. Fgf signalling regulates differential proliferation between the enamel knot and adjacent dental epithelia during tooth development, leading to formation of the dental cusp. The presence of an enamel knot in non-mammalian vertebrates is debated given differences in signalling. Here, we show the conservation and restriction of fgf3, fgf10, and shh to the sites of future dental cusps in the shark (Scyliorhinus canicula), whilst also highlighting striking differences between the shark and mouse. We reveal shifts in tooth size, shape, and cusp number following small molecule perturbations of canonical Wnt signalling. Resulting tooth phenotypes mirror observed effects in mammals, where canonical Wnt has been implicated as an upstream regulator of enamel knot signalling. In silico modelling of shark dental morphogenesis demonstrates how subtle changes in activatory and inhibitory signals can alter tooth shape, resembling developmental phenotypes and cusp shapes observed following experimental Wnt perturbation. Our results support the functional conservation of an enamel knot-like signalling centre throughout vertebrates and suggest that varied tooth types from sharks to mammals follow a similar developmental bauplan. Lineage-specific differences in signalling are not sufficient in refuting homology of this signalling centre, which is likely older than teeth themselves.

    1. Developmental Biology
    2. Evolutionary Biology
    Sophie Pantalacci
    Insight

    The tooth shape of sharks and mice are regulated by a similar signaling center despite their teeth having very different geometries.