1. Cell Biology
  2. Stem Cells and Regenerative Medicine
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The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation

  1. Emma Carley
  2. Rachel Stewart
  3. Abigail G Zieman
  4. Iman Jalilian
  5. Diane E King
  6. Amanda E Zubek
  7. Samantha Lin
  8. Valerie Horsley  Is a corresponding author
  9. Megan C King  Is a corresponding author
  1. Yale School of Medicine, United States
  2. Yale University, United States
Research Article
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Cite this article as: eLife 2021;10:e58541 doi: 10.7554/eLife.58541

Abstract

While the mechanisms by which chemical signals control cell fate have been well studied, how mechanical inputs impact cell fate decisions are not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells, and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate.

Data availability

Sequencing data have been deposited as a single BioProject at NCBI with accession number PRJNA636991

The following data sets were generated

Article and author information

Author details

  1. Emma Carley

    Cell Biology, Yale School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
  2. Rachel Stewart

    Department of Cell Biology, Yale School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
  3. Abigail G Zieman

    Molecular, Cellular and Developmental Biology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8236-207X
  4. Iman Jalilian

    Cell Biology, Yale School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
  5. Diane E King

    Cell Biology, Yale School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
  6. Amanda E Zubek

    Molecular, Cellular and Developmental Biology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  7. Samantha Lin

    Molecular, Cellular and Developmental Biology, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  8. Valerie Horsley

    Molecular, Cellular and Developmental Biology, Yale University, New Haven, United States
    For correspondence
    valerie.horsley@yale.edu
    Competing interests
    Valerie Horsley, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1254-5839
  9. Megan C King

    Department of Cell Biology, Yale School of Medicine, New Haven, United States
    For correspondence
    megan.king@yale.edu
    Competing interests
    Megan C King, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1688-2226

Funding

National Institutes of Health (R01 GM129308)

  • Emma Carley
  • Iman Jalilian
  • Megan C King

American Heart Association (16PRE27460000)

  • Rachel Stewart

Ludwig Family Foundation

  • Rachel Stewart
  • Megan C King

National Institutes of Health (R01 AR060295)

  • Valerie Horsley

National Institutes of Health (R01 AR069550)

  • Valerie Horsley

National Institutes of Health (T32 AR007016)

  • Abigail G Zieman

National Institutes of Health (T32 GM007223)

  • Emma Carley

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 animal care and experimental procedures were conducted in accord with requirements approved by the Institutional Animal Care and Use Committee of Yale University. IACUC Approval 2018-11248.

Reviewing Editor

  1. Elaine Fuchs, Howard Hughes Medical Institute, The Rockefeller University, United States

Publication history

  1. Received: May 5, 2020
  2. Accepted: March 26, 2021
  3. Accepted Manuscript published: March 29, 2021 (version 1)

Copyright

© 2021, Carley 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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