CED-3 caspase acts with miRNAs to regulate non-apoptotic gene expression dynamics for robust development in C. elegans

  1. Benjamin P Weaver
  2. Rebecca Zabinsky
  3. Yi M Weaver
  4. Eui Seung Lee
  5. Ding Xue
  6. Min Han  Is a corresponding author
  1. University of Colorado Boulder, United States
  2. Howard Hughes Medical Institute, University of Colorado Boulder, United States

Abstract

Genetic redundancy and pleiotropism have limited the discovery of functions associated with miRNAs and other regulatory mechanisms. To overcome this, we performed an enhancer screen for developmental defects caused by compromising both global miRISC function and individual genes in C. elegans. Among 126 interactors with miRNAs, we surprisingly found the CED-3 caspase that has only been well studied for its role in promoting apoptosis, mostly through protein activation. We provide evidence for a non-apoptotic function of CED-3 caspase that regulates multiple developmental events through proteolytic inactivation. Specifically, LIN-14, LIN-28 and DISL-2 proteins are known miRNA targets, key regulators of developmental timing, and/or stem cell pluripotency factors involved in miRNA processing. We show CED-3 cleaves these proteins in vitro. We also show CED-3 down-regulates LIN-28 in vivo, possibly rendering it more susceptible to proteasomal degradation. This mechanism may critically contribute to the robustness of gene expression dynamics governing proper developmental control.

Article and author information

Author details

  1. Benjamin P Weaver

    University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Rebecca Zabinsky

    University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yi M Weaver

    Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Eui Seung Lee

    University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ding Xue

    University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Min Han

    Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, United States
    For correspondence
    mhan@colorado.edu
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2014, Weaver 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

  • 2,827
    views
  • 311
    downloads
  • 43
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Benjamin P Weaver
  2. Rebecca Zabinsky
  3. Yi M Weaver
  4. Eui Seung Lee
  5. Ding Xue
  6. Min Han
(2014)
CED-3 caspase acts with miRNAs to regulate non-apoptotic gene expression dynamics for robust development in C. elegans
eLife 3:e04265.
https://doi.org/10.7554/eLife.04265

Share this article

https://doi.org/10.7554/eLife.04265

Further reading

    1. Cell Biology
    2. Developmental Biology
    Jeet H Patel, Mary C Mullins
    Insight

    Disease-causing mutations in the signaling protein BMP4 impair its secretion, but only when it is made as a homodimer.

    1. Cell Biology
    2. Developmental Biology
    Pavan K Nayak, Arul Subramanian, Thomas F Schilling
    Research Article Updated

    Mechanical forces play a critical role in tendon development and function, influencing cell behavior through mechanotransduction signaling pathways and subsequent extracellular matrix (ECM) remodeling. Here, we investigate the molecular mechanisms by which tenocytes in developing zebrafish embryos respond to muscle contraction forces during the onset of swimming and cranial muscle activity. Using genome-wide bulk RNA sequencing of FAC-sorted tenocytes we identify novel tenocyte markers and genes involved in tendon mechanotransduction. Embryonic tendons show dramatic changes in expression of matrix remodeling associated 5b (mxra5b), matrilin 1 (matn1), and the transcription factor kruppel-like factor 2a (klf2a), as muscles start to contract. Using embryos paralyzed either by loss of muscle contractility or neuromuscular stimulation we confirm that muscle contractile forces influence the spatial and temporal expression patterns of all three genes. Quantification of these gene expression changes across tenocytes at multiple tendon entheses and myotendinous junctions reveals that their responses depend on force intensity, duration, and tissue stiffness. These force-dependent feedback mechanisms in tendons, particularly in the ECM, have important implications for improved treatments of tendon injuries and atrophy.