SOX2 regulates acinar cell development in the salivary gland

  1. Elaine Emmerson
  2. Alison May
  3. Sara Nathan
  4. Noel Cruz Pacheco
  5. Carlos O Lizama
  6. Lenka Maliskova
  7. Ann C Zovein
  8. Yin Shen
  9. Marcus O Muench
  10. Sarah M Knox  Is a corresponding author
  1. The University of Edinburgh, United Kingdom
  2. University of California, San Francisco, United States
  3. Blood Systems Research Institute, United States

Abstract

Acinar cells play an essential role in the secretory function of exocrine organs. Despite this requirement, how acinar cells are generated during organogenesis is unclear. Using the acini-ductal network of the developing human and murine salivary gland, we demonstrate an unexpected role for SOX2 and parasympathetic nerves in generating the acinar lineage that has broad implications for epithelial morphogenesis. Despite SOX2 being expressed by progenitors that give rise to both acinar and duct cells, genetic ablation of SOX2 results in a failure to establish acini but not ducts. Furthermore, we show that SOX2 targets acinar specific genes and is essential for the survival of acinar but not ductal cells. Finally, we illustrate an unexpected and novel role for peripheral nerves in the creation of acini throughout development via regulation of SOX2. Thus, SOX2 is a master regulator of the acinar cell lineage essential to the establishment of a functional organ.

Article and author information

Author details

  1. Elaine Emmerson

    The MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5902-3368
  2. Alison May

    Program in Craniofacial Biology, Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sara Nathan

    Program in Craniofacial Biology, Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Noel Cruz Pacheco

    Program in Craniofacial Biology, Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Carlos O Lizama

    Program in Craniofacial Biology, Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Lenka Maliskova

    Institute of Human Genetics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ann C Zovein

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yin Shen

    Institute of Human Genetics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Marcus O Muench

    Blood Systems Research Institute, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8946-6605
  10. Sarah M Knox

    Program in Craniofacial Biology, Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    For correspondence
    sarah.knox@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7567-083X

Funding

National Institute of Dental and Craniofacial Research (R01DE024188)

  • Elaine Emmerson
  • Alison May
  • Sara Nathan
  • Noel Cruz Pacheco
  • Sarah M Knox

California Institute for Regenerative Medicine

  • Elaine Emmerson

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

Reviewing Editor

  1. Valerie Horsley, Yale University, United States

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 (#AN107810and AN111238) of the University of California San Francisco.

Version history

  1. Received: March 8, 2017
  2. Accepted: June 13, 2017
  3. Accepted Manuscript published: June 17, 2017 (version 1)
  4. Version of Record published: July 5, 2017 (version 2)

Copyright

© 2017, Emmerson 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

  • 4,215
    Page views
  • 588
    Downloads
  • 71
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, 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. Elaine Emmerson
  2. Alison May
  3. Sara Nathan
  4. Noel Cruz Pacheco
  5. Carlos O Lizama
  6. Lenka Maliskova
  7. Ann C Zovein
  8. Yin Shen
  9. Marcus O Muench
  10. Sarah M Knox
(2017)
SOX2 regulates acinar cell development in the salivary gland
eLife 6:e26620.
https://doi.org/10.7554/eLife.26620

Share this article

https://doi.org/10.7554/eLife.26620

Further reading

    1. Developmental Biology
    2. Immunology and Inflammation
    Amir Hossein Kayvanjoo, Iva Splichalova ... Elvira Mass
    Research Article Updated

    During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.

    1. Developmental Biology
    2. Neuroscience
    Smrithi Prem, Bharati Dev ... Emanuel DiCicco-Bloom
    Research Article Updated

    Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite outgrowth and migration even though whole genome sequencing demonstrates no genetic overlap between the datasets. To identify signaling differences that may contribute to these developmental defects, an unbiased phospho-(p)-proteome screen was performed. Surprisingly despite the genetic heterogeneity, hundreds of shared p-peptides were identified between autism subtypes including the mTOR pathway. mTOR signaling alterations were confirmed in all NPCs across both ASD subtypes, and mTOR modulation rescued ASD phenotypes and reproduced autism NPC-associated phenotypes in control NPCs. Thus, our studies demonstrate that genetically distinct ASD subtypes have common defects in neurite outgrowth and migration which are driven by the shared pathogenic mechanism of mTOR signaling dysregulation.