Embryonic transcription factor expression in mice predicts medial amygdala neuronal identity and sex-specific responses to innate behavioral cues

  1. Julieta E Lischinsky
  2. Katie Sokolowski
  3. Peijun Li
  4. Shigeyuki Esumi
  5. Yasmin Kamal
  6. Meredith Goodrich
  7. Livio Oboti
  8. Timothy R Hammond
  9. Meera Krishnamoorthy
  10. Daniel Feldman
  11. Molly Huntsman
  12. Judy Liu
  13. Joshua G Corbin  Is a corresponding author
  1. The George Washington University, United States
  2. Children's National Medical Center, United States
  3. University of Colorado School of Medicine, Aurora, United States

Abstract

The medial subnucleus of the amygdala (MeA) plays a central role in processing sensory cues required for innate behaviors. However, whether there is a link between developmental programs and the emergence of inborn behaviors remains unknown. Our previous studies revealed that the telencephalic preoptic area (POA) embryonic niche is a novel source of MeA destined progenitors. Here, we show that the POA is comprised of distinct progenitor pools complementarily marked by the transcription factors Dbx1 and Foxp2. As determined by molecular and electrophysiological criteria this embryonic parcellation predicts postnatal MeA inhibitory neuronal subtype identity. We further find that Dbx1-derived and Foxp2+ cells in the MeA are differentially activated in response to innate behavioral cues in a sex-specific manner. Thus, developmental transcription factor expression is predictive of MeA neuronal identity and sex-specific neuronal responses, providing a potential developmental logic for how innate behaviors could be processed by different MeA neuronal subtypes.

Article and author information

Author details

  1. Julieta E Lischinsky

    Institute for Biomedical Sciences, The George Washington University, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1664-6642
  2. Katie Sokolowski

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Peijun Li

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shigeyuki Esumi

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yasmin Kamal

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Meredith Goodrich

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Livio Oboti

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Timothy R Hammond

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Meera Krishnamoorthy

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Daniel Feldman

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Molly Huntsman

    Department of Pediatrics, University of Colorado School of Medicine, Aurora, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Judy Liu

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Joshua G Corbin

    Center for Neuroscience Research, Children's National Medical Center, Washington DC, United States
    For correspondence
    JCorbin@cnmcresearch.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0122-4324

Funding

National Institute on Drug Abuse (R01 NIDA020140)

  • Joshua G Corbin

Intellectual and Developmental Disabilities Research Center (IDDRC P30HD040677)

  • Joshua G Corbin

National Institute on Deafness and Other Communication Disorders (R01 DC012050)

  • Joshua G Corbin

National Institute on Drug Abuse (F32 DA035754)

  • Katie Sokolowski

Goldwin Foundation Grant for Pediatric Epilepsy

  • Judy Liu

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 animal procedures were approved by the Children's National Medical Center's Institutional Animal Care (Animal Welfare Assurance Number: A3338-01) and Use Committee (IACUC) protocols (#00030435) and conformed to NIH Guidelines for animal use. All surgery was performed under ketamine/xylazine cocktail anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Carol A Mason, Columbia University, United States

Publication history

  1. Received: August 26, 2016
  2. Accepted: February 26, 2017
  3. Accepted Manuscript published: February 28, 2017 (version 1)
  4. Accepted Manuscript updated: March 13, 2017 (version 2)
  5. Version of Record published: April 7, 2017 (version 3)

Copyright

© 2017, Lischinsky 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.

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  1. Julieta E Lischinsky
  2. Katie Sokolowski
  3. Peijun Li
  4. Shigeyuki Esumi
  5. Yasmin Kamal
  6. Meredith Goodrich
  7. Livio Oboti
  8. Timothy R Hammond
  9. Meera Krishnamoorthy
  10. Daniel Feldman
  11. Molly Huntsman
  12. Judy Liu
  13. Joshua G Corbin
(2017)
Embryonic transcription factor expression in mice predicts medial amygdala neuronal identity and sex-specific responses to innate behavioral cues
eLife 6:e21012.
https://doi.org/10.7554/eLife.21012
  1. Further reading

Further reading

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    Research Article Updated

    Defining the origin of neuronal diversity is a major challenge in developmental neurobiology. The Drosophila visual system is an excellent paradigm to study how cellular diversity is generated. Photoreceptors from the eye disc grow their axons into the optic lobe and secrete Hedgehog (Hh) to induce the lamina, such that for every unit eye there is a corresponding lamina unit made up of post-mitotic precursors stacked into columns. Each differentiated column contains five lamina neuron types (L1-L5), making it the simplest neuropil in the optic lobe, yet how this diversity is generated was unknown. Here, we found that Hh pathway activity is graded along the distal-proximal axis of lamina columns, and further determined that this gradient in pathway activity arises from a gradient of Hh ligand. We manipulated Hh pathway activity cell autonomously in lamina precursors and non-cell autonomously by inactivating the Hh ligand and by knocking it down in photoreceptors. These manipulations showed that different thresholds of activity specify unique cell identities, with more proximal cell types specified in response to progressively lower Hh levels. Thus, our data establish that Hh acts as a morphogen to pattern the lamina. Although this is the first such report during Drosophila nervous system development, our work uncovers a remarkable similarity with the vertebrate neural tube, which is patterned by Sonic Hh. Altogether, we show that differentiating neurons can regulate the neuronal diversity of their distant target fields through morphogen gradients.

    1. Developmental Biology
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    Anadika R Prasad, Inês Lago-Baldaia ... Vilaiwan M Fernandes
    Research Article Updated

    Neural circuit formation and function require that diverse neurons are specified in appropriate numbers. Known strategies for controlling neuronal numbers involve regulating either cell proliferation or survival. We used the Drosophila visual system to probe how neuronal numbers are set. Photoreceptors from the eye-disc induce their target field, the lamina, such that for every unit eye there is a corresponding lamina unit (column). Although each column initially contains ~6 post-mitotic lamina precursors, only 5 differentiate into neurons, called L1-L5; the ‘extra’ precursor, which is invariantly positioned above the L5 neuron in each column, undergoes apoptosis. Here, we showed that a glial population called the outer chiasm giant glia (xgO), which resides below the lamina, secretes multiple ligands to induce L5 differentiation in response to epidermal growth factor (EGF) from photoreceptors. By forcing neuronal differentiation in the lamina, we uncovered that though fated to die, the ‘extra’ precursor is specified as an L5. Therefore, two precursors are specified as L5s but only one differentiates during normal development. We found that the row of precursors nearest to xgO differentiate into L5s and, in turn, antagonise differentiation signalling to prevent the ‘extra’ precursors from differentiating, resulting in their death. Thus, an intricate interplay of glial signals and feedback from differentiating neurons defines an invariant and stereotyped pattern of neuronal differentiation and programmed cell death to ensure that lamina columns each contain exactly one L5 neuron.