Forkhead transcription factor FKH-8 cooperates with RFX in the direct regulation of sensory cilia in C. elegans
- Instituto de Biomedicina de Valencia, Spain
- Karolinska Institute, Sweden
- 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 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.
-
scRNAseq L2 stageNCBI Gene Expression Omnibus, GSE126954.
-
scRNAseq L4 stageNCBI Gene Expression Omnibus, GSE136049.
Article and author information
Author details
Rebeca Brocal-Ruiz
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.
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.
Metrics
-
- 1,160
- views
-
- 175
- downloads
-
- 5
- 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)
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
Further reading
-
- Developmental Biology
Although the impact of gender-affirming hormone therapy (GAHT) on spermatogenesis in trans women has already been studied, data on its precise effects on the testicular environment is poor. Therefore, this study aimed to characterize, through histological and transcriptomic analysis, the spermatogonial stem cell niche of 106 trans women who underwent standardized GAHT, comprising estrogens and cyproterone acetate. A partial dedifferentiation of Sertoli cells was observed, marked by the co-expression of androgen receptor and anti-Müllerian hormone which mirrors the situation in peripubertal boys. The Leydig cells also exhibited a distribution analogous to peripubertal tissue, accompanied by a reduced insulin-like factor 3 expression. Although most peritubular myoid cells expressed alpha-smooth muscle actin 2, the expression pattern was disturbed. Besides this, fibrosis was particularly evident in the tubular wall and the lumen was collapsing in most participants. A spermatogenic arrest was also observed in all participants. The transcriptomic profile of transgender tissue confirmed a loss of mature characteristics - a partial rejuvenation - of the spermatogonial stem cell niche and, in addition, detected inflammation processes occurring in the samples. The present study shows that GAHT changes the spermatogonial stem cell niche by partially rejuvenating the somatic cells and inducing fibrotic processes. These findings are important to further understand how estrogens and testosterone suppression affect the testis environment, and in the case of orchidectomized testes as medical waste material, their potential use in research.
-
- Computational and Systems Biology
- Developmental Biology
The Notch signaling pathway uses families of ligands and receptors to transmit signals to nearby cells. These components are expressed in diverse combinations in different cell types, interact in a many-to-many fashion, both within the same cell (in cis) and between cells (in trans), and their interactions are modulated by Fringe glycosyltransferases. A fundamental question is how the strength of Notch signaling depends on which pathway components are expressed, at what levels, and in which cells. Here, we used a quantitative, bottom-up, cell-based approach to systematically characterize trans-activation, cis-inhibition, and cis-activation signaling efficiencies across a range of ligand and Fringe expression levels in Chinese hamster and mouse cell lines. Each ligand (Dll1, Dll4, Jag1, and Jag2) and receptor variant (Notch1 and Notch2) analyzed here exhibited a unique profile of interactions, Fringe dependence, and signaling outcomes. All four ligands were able to bind receptors in cis and in trans, and all ligands trans-activated both receptors, although Jag1-Notch1 signaling was substantially weaker than other ligand-receptor combinations. Cis-interactions were predominantly inhibitory, with the exception of the Dll1- and Dll4-Notch2 pairs, which exhibited cis-activation stronger than trans-activation. Lfng strengthened Delta-mediated trans-activation and weakened Jagged-mediated trans-activation for both receptors. Finally, cis-ligands showed diverse cis-inhibition strengths, which depended on the identity of the trans-ligand as well as the receptor. The map of receptor-ligand-Fringe interaction outcomes revealed here should help guide rational perturbation and control of the Notch pathway.
