Cyclin-dependent kinase control of motile ciliogenesis

  1. Eszter K Vladar  Is a corresponding author
  2. Miranda B Stratton
  3. Maxwell L Saal
  4. Glicella Salazar-De Simone
  5. Xiangyuan Wang
  6. Debra Wolgemuth
  7. Tim Stearns
  8. Jeffrey D Axelrod
  1. University of Colorado School of Medicine, United States
  2. Stanford University, United States
  3. Columbia University Medical Center, United States
  4. Stanford University School of Medicine, United States

Abstract

Cycling cells maintain centriole number at precisely two per cell in part by limiting their duplication to S phase under the control of the cell cycle machinery. In contrast, postmitotic multiciliated cells (MCCs) uncouple centriole assembly from cell cycle progression and produce hundreds of centrioles in the absence of DNA replication to serve as basal bodies for motile cilia. Although some cell cycle regulators have previously been implicated in motile ciliogenesis, how the cell cycle machinery is employed to amplify centrioles is unclear. We use transgenic mice and primary airway epithelial cell culture to show that Cdk2, the kinase responsible for the G1 to S phase transition, is also required in MCCs to initiate motile ciliogenesis. While Cdk2 is coupled with Cyclins E and A2 during cell division, Cyclin A1 is required during ciliogenesis, contributing to an alternative regulatory landscape that facilitates centriole amplification without DNA replication.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Eszter K Vladar

    Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, United States
    For correspondence
    eszter.vladar@ucdenver.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4160-8894
  2. Miranda B Stratton

    Department of Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Maxwell L Saal

    Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Glicella Salazar-De Simone

    Center for Radiological Research, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xiangyuan Wang

    Department of Genetics and Development, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Debra Wolgemuth

    Department of Genetics and Development, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Tim Stearns

    Department of Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0671-6582
  8. Jeffrey D Axelrod

    Department of Pathology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (R01GM052022)

  • Tim Stearns

National Institutes of Health (R01GM121424)

  • Tim Stearns

National Institutes of Health (R01GM098582)

  • Jeffrey D Axelrod

National Institutes of Health (1R01HD034915)

  • Debra Wolgemuth

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

Reviewing Editor

  1. Jay Rajagopal, Harvard University, United States

Ethics

Animal experimentation: All procedures involving animals were approved by the Institutional Animal Care and Use Committee of Stanford University School of Medicine (#17926) in accordance with established guidelines for animal care.

Version history

  1. Received: March 3, 2018
  2. Accepted: August 26, 2018
  3. Accepted Manuscript published: August 28, 2018 (version 1)
  4. Version of Record published: September 19, 2018 (version 2)

Copyright

© 2018, Vladar 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

  • 2,555
    Page views
  • 516
    Downloads
  • 27
    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. Eszter K Vladar
  2. Miranda B Stratton
  3. Maxwell L Saal
  4. Glicella Salazar-De Simone
  5. Xiangyuan Wang
  6. Debra Wolgemuth
  7. Tim Stearns
  8. Jeffrey D Axelrod
(2018)
Cyclin-dependent kinase control of motile ciliogenesis
eLife 7:e36375.
https://doi.org/10.7554/eLife.36375

Share this article

https://doi.org/10.7554/eLife.36375

Further reading

    1. Cell Biology
    Kazuki Hanaoka, Kensuke Nishikawa ... Kouichi Funato
    Research Article

    Membrane contact sites (MCSs) are junctures that perform important roles including coordinating lipid metabolism. Previous studies have indicated that vacuolar fission/fusion processes are coupled with modifications in the membrane lipid composition. However, it has been still unclear whether MCS-mediated lipid metabolism controls the vacuolar morphology. Here, we report that deletion of tricalbins (Tcb1, Tcb2, and Tcb3), tethering proteins at endoplasmic reticulum (ER)–plasma membrane (PM) and ER–Golgi contact sites, alters fusion/fission dynamics and causes vacuolar fragmentation in the yeast Saccharomyces cerevisiae. In addition, we show that the sphingolipid precursor phytosphingosine (PHS) accumulates in tricalbin-deleted cells, triggering the vacuolar division. Detachment of the nucleus–vacuole junction (NVJ), an important contact site between the vacuole and the perinuclear ER, restored vacuolar morphology in both cells subjected to high exogenous PHS and Tcb3-deleted cells, supporting that PHS transport across the NVJ induces vacuole division. Thus, our results suggest that vacuolar morphology is maintained by MCSs through the metabolism of sphingolipids.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Monica Salinas-Pena, Elena Rebollo, Albert Jordan
    Research Article

    Histone H1 participates in chromatin condensation and regulates nuclear processes. Human somatic cells may contain up to seven histone H1 variants, although their functional heterogeneity is not fully understood. Here, we have profiled the differential nuclear distribution of the somatic H1 repertoire in human cells through imaging techniques including super-resolution microscopy. H1 variants exhibit characteristic distribution patterns in both interphase and mitosis. H1.2, H1.3, and H1.5 are universally enriched at the nuclear periphery in all cell lines analyzed and co-localize with compacted DNA. H1.0 shows a less pronounced peripheral localization, with apparent variability among different cell lines. On the other hand, H1.4 and H1X are distributed throughout the nucleus, being H1X universally enriched in high-GC regions and abundant in the nucleoli. Interestingly, H1.4 and H1.0 show a more peripheral distribution in cell lines lacking H1.3 and H1.5. The differential distribution patterns of H1 suggest specific functionalities in organizing lamina-associated domains or nucleolar activity, which is further supported by a distinct response of H1X or phosphorylated H1.4 to the inhibition of ribosomal DNA transcription. Moreover, H1 variants depletion affects chromatin structure in a variant-specific manner. Concretely, H1.2 knock-down, either alone or combined, triggers a global chromatin decompaction. Overall, imaging has allowed us to distinguish H1 variants distribution beyond the segregation in two groups denoted by previous ChIP-Seq determinations. Our results support H1 variants heterogeneity and suggest that variant-specific functionality can be shared between different cell types.