Forkhead transcription factor FKH-8 cooperates with RFX in the direct regulation of sensory cilia in C. elegans
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
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
- Douglas Portman, University of Rochester, United States
Version history
- Preprint posted: September 15, 2021 (view preprint)
- Received: May 26, 2023
- Accepted: July 7, 2023
- Accepted Manuscript published: July 14, 2023 (version 1)
- 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.
Metrics
-
- 640
- Page views
-
- 118
- Downloads
-
- 0
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
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)
Further reading
-
- Developmental Biology
- Stem Cells and Regenerative Medicine
During evolution, animals have returned from land to water, adapting with morphological modifications to life in an aquatic environment. We compared the osteochondral units of the humeral head of marine and terrestrial mammals across species spanning a wide range of body weights, focusing on microstructural organization and biomechanical performance. Aquatic mammals feature cartilage with essentially random collagen fiber configuration, lacking the depth-dependent, arcade-like organization characteristic of terrestrial mammalian species. They have a less stiff articular cartilage at equilibrium with a significantly lower peak modulus, and at the osteochondral interface do not have a calcified cartilage layer, displaying only a thin, highly porous subchondral bone plate. This totally different constitution of the osteochondral unit in aquatic mammals reflects that accommodation of loading is the primordial function of the osteochondral unit. Recognizing the crucial importance of the microarchitecture-function relationship is pivotal for understanding articular biology and, hence, for the development of durable functional regenerative approaches for treatment of joint damage, which are thus far lacking.
-
- Cell Biology
- Developmental Biology
An animal’s responses to environmental cues are critical for its reproductive program. Thus, a mechanism that allows the animal to sense and adjust to its environment should make for a more efficient reproductive physiology. Here, we demonstrate that in Caenorhabditis elegans specific sensory neurons influence onset of oogenesis through insulin signaling in response to food-derived cues. The chemosensory neurons ASJ modulate oogenesis onset through the insulin-like peptide (ILP) INS-6. In contrast, other sensory neurons, the olfactory neurons AWA, regulate food type-dependent differences in C. elegans fertilization rates, but not onset of oogenesis. AWA modulates fertilization rates at least partly in parallel to insulin receptor signaling, since the insulin receptor DAF-2 regulates fertilization independently of food type, which requires ILPs other than INS-6. Together our findings suggest that optimal reproduction requires the integration of diverse food-derived inputs through multiple neuronal signals acting on the C. elegans germline.