Forkhead transcription factor FKH-8 cooperates with RFX in the direct regulation of sensory cilia in C. elegans

  1. Rebeca Brocal-Ruiz
  2. Ainara Esteve-Serrano
  3. Carlos Mora-Martínez
  4. Maria Luisa Franco-Rivadeneira
  5. Peter Swoboda
  6. Juan Tena
  7. Marçal Vilar
  8. Nuria Flames  Is a corresponding author
  1. Instituto de Biomedicina de Valencia, Spain
  2. Karolinska Institute, Sweden
  3. Centro Andaluz de Biología del Desarrollo, Spain

Abstract

Cilia, either motile or non-motile (a.k.a primary or sensory), are complex evolutionarily conserved eukaryotic structures composed of hundreds of proteins required for their assembly, structure and function that are collectively known as the ciliome. Ciliome gene mutations underlie a group of pleiotropic genetic diseases known as ciliopathies. Proper cilium function requires the tight coregulation of ciliome gene transcription, which is only fragmentarily understood. RFX transcription factors (TF) have an evolutionarily conserved role in the direct activation of ciliome genes both in motile and non-motile cilia cell-types. In vertebrates, FoxJ1 and FoxN4 Forkhead (FKH) TFs work with RFX in the direct activation of ciliome genes, exclusively in motile cilia cell-types. No additional TFs have been described to act together with RFX in primary cilia cell-types in any organism. Here we describe FKH-8, a FKH TF, as a direct regulator of the sensory ciliome genes in Caenorhabditis elegans. FKH-8 is expressed in all ciliated neurons in C. elegans, binds the regulatory regions of ciliome genes, regulates ciliome gene expression, cilium morphology and a wide range of behaviours mediated by sensory ciliated neurons. FKH-8 and DAF-19 (C. elegans RFX) physically interact and synergistically regulate ciliome gene expression. C. elegans FKH-8 function can be replaced by mouse FOXJ1 and FOXN4 but not by other members of other mouse FKH subfamilies. In conclusion, RFX and FKH TF families act jointly as direct regulators of ciliome genes also in sensory ciliated cell types suggesting that this regulatory logic could be an ancient trait predating functional cilia sub-specialization.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data file 1 and 3 contain all raw data and statistical analysis for figures, Source Data file 2 contains information regarding gene lists and bioinformatics analysis, Source Data file 4 has all the information regarding plasmids, strains and primers.

The following previously published data sets were used
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    2. Hitz BC
    3. Sloan CA
    4. Chan ET
    5. et al
    (2018) The 1168 Encyclopedia of DNA elements (ENCODE): Data portal update.
    ENCODE database:ENCFF818YOR, ENCFF549ZSK, ENCFF694MNH, ENCFF552OQU, ENCFF357NSB, ENCFF496CFD, ENCFF092YIJ, ENCFF799WBN, ENCFF810HSZ, ENCFF554KQD, ENCFF390OSN, ENCFF433BEM, ENCFF960EQR, ENCFF792JXA, ENCFF761XWC, ENCFF384GUN, ENCFF803WZH, ENCFF448URK, ENCFF827XAE, ENCFF595SML, ENCFF803QRP, ENCFF587FBJ, ENCFF789TVB, ENCFF816EMR, ENCFF554VDX, ENCFF241SCQ, ENCFF202WJY, ENCFF017FUN, ENCFF798RPP, ENCFF541MIX, ENCFF176UKF, ENCFF947PYR, ENCFF786PUW, ENCFF400VSR, ENCFF786PQH, ENCFF398DRS, ENCFF868IPD, ENCFF409ZRG, ENCFF303QBQ, ENCFF671UBP, ENCFF273RBS, ENCFF995PYF, ENCFF897INS, ENCFF489OMV.

Article and author information

Author details

  1. Rebeca Brocal-Ruiz

    Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3375-942X
  2. Ainara Esteve-Serrano

    Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Carlos Mora-Martínez

    Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Maria Luisa Franco-Rivadeneira

    Molecular Basis of Neurodegeneration Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Peter Swoboda

    Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6416-8572
  6. Juan Tena

    Consejo Superior de Investigaciones Científicas, Centro Andaluz de Biología del Desarrollo, Seville, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Marçal Vilar

    Molecular Basis of Neurodegeneration Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9376-6544
  8. Nuria Flames

    Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    For correspondence
    nflames@ibv.csic.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0961-0609

Funding

HORIZON EUROPE European Research Council (ERC-2020-COG-101002203(NEUROCODE))

  • Rebeca Brocal-Ruiz
  • Ainara Esteve-Serrano
  • Carlos Mora-Martínez
  • Nuria Flames

Ministerio de ciencia e innovacion (BES-2015-072799)

  • Rebeca Brocal-Ruiz

Ministerio de ciencia e innovacion (PID2020-115635RB-I00)

  • Rebeca Brocal-Ruiz
  • Ainara Esteve-Serrano
  • Carlos Mora-Martínez
  • Nuria Flames

European Research Council (ERC-2011-StG_20101109)

  • Rebeca Brocal-Ruiz
  • Ainara Esteve-Serrano
  • Carlos Mora-Martínez
  • Nuria Flames

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

Reviewing Editor

  1. Douglas Portman, University of Rochester, United States

Version history

  1. Preprint posted: September 15, 2021 (view preprint)
  2. Received: May 26, 2023
  3. Accepted: July 7, 2023
  4. Accepted Manuscript published: July 14, 2023 (version 1)
  5. Version of Record published: August 1, 2023 (version 2)

Copyright

© 2023, Brocal-Ruiz 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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  1. Rebeca Brocal-Ruiz
  2. Ainara Esteve-Serrano
  3. Carlos Mora-Martínez
  4. Maria Luisa Franco-Rivadeneira
  5. Peter Swoboda
  6. Juan Tena
  7. Marçal Vilar
  8. Nuria Flames
(2023)
Forkhead transcription factor FKH-8 cooperates with RFX in the direct regulation of sensory cilia in C. elegans
eLife 12:e89702.
https://doi.org/10.7554/eLife.89702

Share this article

https://doi.org/10.7554/eLife.89702

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