Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks

  1. Kelsey H Elliott
  2. Xiaoting Chen
  3. Joseph Salomone
  4. Praneet Chaturvedi
  5. Preston A Schultz
  6. Sai K Balchand
  7. Jeffrey D Servetas
  8. Aimée zuniga
  9. Rolf Zeller
  10. Brian Gebelein
  11. Matthew T Weirauch
  12. Kevin A Peterson  Is a corresponding author
  13. Samantha A Brugmann  Is a corresponding author
  1. Cincinnati Children's Hospital Medical Center, United States
  2. The Jackson Laboratory, United States
  3. University of Basel, Switzerland
  4. Harvard University, United States

Abstract

Despite a common understanding that Gli TFs are utilized to reiterate a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. Using the mouse model (Mus musculus), we demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the basic helix-loop-helix TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied by Gli3 and Hand2 uncovered mandibular-specific, low-affinity, 'divergent' Gli binding motifs (<strong>d</strong>GBMs). Functional validation revealed these <strong>d</strong>GBMs conveyed synergistic activation of Gli targets essential for mandibular patterning and development. In summary, this work elucidates a novel, sequence-dependent mechanism for Gli transcriptional activity within the craniofacial complex that is independent of a graded Hh signal.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE141431, GSE141173.ChIP data have been deposited in GEO under accession code GSE146961All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1,5,8,9, Figure 1-figure supplement 1, Figure 8-figure supplement 2, and Figure 9-figure supplement 1

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Kelsey H Elliott

    Pediatrics - Division of Developmental Biology; Surgery- Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xiaoting Chen

    Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Joseph Salomone

    Pediatrics - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Praneet Chaturvedi

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Preston A Schultz

    Pediatrics - Division of Developmental Biology; Surgery- Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sai K Balchand

    Pediatrics - Division of Developmental Biology; Surgery- Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jeffrey D Servetas

    The Jackson Laboratory, The Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Aimée zuniga

    University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  9. Rolf Zeller

    University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  10. Brian Gebelein

    Pediatrics - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9791-9061
  11. Matthew T Weirauch

    Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Kevin A Peterson

    Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
    For correspondence
    kevin.peterson@jax.org
    Competing interests
    The authors declare that no competing interests exist.
  13. Samantha A Brugmann

    Pediatrics - Division of Developmental Biology; Surgery- Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    For correspondence
    samantha.brugmann@cchmc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6860-6450

Funding

National Institutes of Health (R35DE027557)

  • Samantha A Brugmann

National Institutes of Health (R01GM124251)

  • Kevin A Peterson

National Institutes of Health (F31DE027872)

  • Kelsey H Elliott

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (IACUC2017-0063) of Cincinnati Children's Hospital Medical Center.

Reviewing Editor

  1. Kathryn Song Eng Cheah, The University of Hong Kong, Hong Kong

Version history

  1. Received: February 27, 2020
  2. Accepted: October 1, 2020
  3. Accepted Manuscript published: October 2, 2020 (version 1)
  4. Version of Record published: October 14, 2020 (version 2)

Copyright

© 2020, Elliott 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

  • 2,052
    Page views
  • 313
    Downloads
  • 7
    Citations

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

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. Kelsey H Elliott
  2. Xiaoting Chen
  3. Joseph Salomone
  4. Praneet Chaturvedi
  5. Preston A Schultz
  6. Sai K Balchand
  7. Jeffrey D Servetas
  8. Aimée zuniga
  9. Rolf Zeller
  10. Brian Gebelein
  11. Matthew T Weirauch
  12. Kevin A Peterson
  13. Samantha A Brugmann
(2020)
Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks
eLife 9:e56450.
https://doi.org/10.7554/eLife.56450

Further reading

    1. Developmental Biology
    2. Neuroscience
    Igor Y Iskusnykh, Nikolai Fattakhov ... Victor V Chizhikov
    Research Article

    Development of the nervous system depends on signaling centers – specialized cellular populations that produce secreted molecules to regulate neurogenesis in the neighboring neuroepithelium. In some cases, signaling center cells also differentiate to produce key types of neurons. The formation of a signaling center involves its induction, the maintenance of expression of its secreted molecules, and cell differentiation and migration events. How these distinct processes are coordinated during signaling center development remains unknown. By performing studies in mice, we show that Lmx1a acts as a master regulator to orchestrate the formation and function of the cortical hem (CH), a critical signaling center that controls hippocampus development. Lmx1a co-regulates CH induction, its Wnt signaling, and the differentiation and migration of CH-derived Cajal–Retzius neurons. Combining RNAseq, genetic, and rescue experiments, we identified major downstream genes that mediate distinct Lmx1a-dependent processes. Our work revealed that signaling centers in the mammalian brain employ master regulatory genes and established a framework for analyzing signaling center development.

    1. Developmental Biology
    2. Evolutionary Biology
    Salvatore D'Aniello, Stephanie Bertrand, Hector Escriva
    Feature Article

    Cephalochordates and tunicates represent the only two groups of invertebrate chordates, and extant cephalochordates – commonly known as amphioxus or lancelets – are considered the best proxy for the chordate ancestor, from which they split around 520 million years ago. Amphioxus has been an important organism in the fields of zoology and embryology since the 18th century, and the morphological and genomic simplicity of cephalochordates (compared to vertebrates) makes amphioxus an attractive model for studying chordate biology at the cellular and molecular levels. Here we describe the life cycle of amphioxus, and discuss the natural histories and habitats of the different species of amphioxus. We also describe their use as laboratory animal models, and discuss the techniques that have been developed to study different aspects of amphioxus.