Correction: Foxn4 promotes gene expression required for the formation of multiple motile cilia

Campbell, Evan P.; Quigley, Ian K.; Kintner, Chris

doi:10.1242/dev.149567

Cited by 10 publications

(11 citation statements)

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“…Importantly, vertebrate sensory ciliogenesis is unaffected in FoxJ1 loss of function mutants (Choksi et al, 2014); thus, FoxJ1 role as a master regulator of ciliogenesis is restricted to motile ciliary cell types. In Xenopus, FoxN4 binds similar genomic regions to FoxJ1 and it is also required for motile ciliome gene expression (Campbell et al, 2016). We find both FOXJ1 and FOXN4, but not FOXI1, which has not been described to be involved in ciliogenesis, are able to functionally substitute FKH-8.…”

Section: Role Of Fkh Tfs In the Transcriptional Regulation Of Ciliome Genes Both In Motile And Sensory Cilia Cell Typesmentioning

confidence: 63%

“…We find this to be the case as FoxJ1 cDNA expression under the dopaminergic promoter dat-1 rescues ift-20 expression similarly to fkh-8 cDNA (Figure 7A-C). In Xenopus, another FKH TF, FoxN4, binds similar genomic regions to FoxJ1 and it is also required for direct ciliome gene expression in motile multiciliated cells (Campbell et al, 2016). We find A) daf-19 locus codes for five different daf-19 isoforms.…”

Section: Mouse Foxj1 and Foxn4 Master Regulators Of Motile Ciliome Can Functionally Replace Fkh-8mentioning

confidence: 95%

“…In addition, functional paralog substitutions among TFs of the same family have been described to occur in evolution (Tarashansky et al, 2021). Importantly, FoxJ1 and FoxN4 mutants do not show ciliome gene expression defects in non-motile ciliated cell types (Brody et al, 2000;Campbell et al, 2016;Chen et al, 1998;Stubbs et al, 2008;Yu et al, 2008). Other members of FoxJ and FoxN subfamilies are broadly expressed in mouse neurons, which all display primary cilia (Zeisel et al, 2018).…”

Section: Role Of Fkh Tfs In Ciliome Regulation Of Primary Cilia Cell Typesmentioning

confidence: 99%

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Forkhead transcription factor FKH-8 is a master regulator of primary cilia in C. elegans

Brocal-Ruiz

Esteve-Serrano

Mora‐Martinez

et al. 2021

Preprint

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Cilia, either motile or non-motile (a.k.a primary or sensory), are complex evolutionary conserved eukaryotic structures composed of hundreds of proteins required for their assembly, structure and function that are collectively known as the ciliome. Ciliome 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 master regulator of the primary ciliome 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 cilia. Importantly, we find FKH-8 function can be replaced by mouse FOXJ1 and FOXN4 but not by members of other mouse FKH subfamilies. In conclusion, our results show that RFX and FKH TF families act as master regulators of ciliogenesis also in sensory ciliated cell types and suggest that this regulatory logic could be an ancient trait predating functional cilia sub-specialization.

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Section: Role Of Fkh Tfs In the Transcriptional Regulation Of Ciliome Genes Both In Motile And Sensory Cilia Cell Typesmentioning

confidence: 63%

Section: Mouse Foxj1 and Foxn4 Master Regulators Of Motile Ciliome Can Functionally Replace Fkh-8mentioning

confidence: 95%

Section: Role Of Fkh Tfs In Ciliome Regulation Of Primary Cilia Cell Typesmentioning

confidence: 99%

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Forkhead transcription factor FKH-8 is a master regulator of primary cilia in C. elegans

Brocal-Ruiz

Esteve-Serrano

Mora‐Martinez

et al. 2021

Preprint

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“…A number of candidate transcription factors were identified for the control of the putative resistant cells that express core components of primary cilia ( figure 6B). These included RFX3, which is a master regulator of cilia formation (Légaré et al, 2017), and also MYB and FOXN4, which have roles in ciliagenesis and promoting S-phase of the cell cycle (Campbell, Quigley, & Kintner, 2017;Tan et al, 2013). Further, the transcriptional repressor, E2F7, was significantly expressed and transcriptionally activated in the cilia associated cells.…”

Section: Discussionmentioning

confidence: 99%

Single cell transcriptomics reveals molecular subtype and functional heterogeneity in models of breast cancer

Roden

Baker

Elsworth

et al. 2018

Preprint

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Breast cancer has long been classified into a number of molecular subtypes that predict prognosis and therefore influence clinical treatment decisions. Cellular heterogeneity is also evident in breast cancers and plays a key role in the development, evolution and metastatic progression of many cancers. How clinical heterogeneity relates to cellular heterogeneity is poorly understood, so we approached this question using single cell gene expression analysis of well established in vitro and in vivo models of disease. To explore the cellular heterogeneity in breast cancer we first examined a panel of genes that define the PAM50 classifier of molecular subtype. Five breast cancer cell line models (MCF7, BT474, SKBR3, MDA--MB--231, and MDA--MB--468) were selected as representatives of the intrinsic molecular subtypes (luminal A and B,. Single cell multiplex RT--PCR was used to isolate and quantify the gene expression of single cells from each of these models, and the PAM50 classifier applied. Using this approach, we identified heterogeneity of intrinsic subtypes at single--cell level, indicating that cells with different subtypes exist within a cell line. Using the Chromium 10X system, this study was extended into thousands of cells from the MCF7 cell--line and an ER+ patient derived xenograft (PDX) model and again identified significant intra--tumour heterogeneity of molecular subtype. Estrogen Receptor (ER) is an important driver and therapeutic target in many breast cancers. It is heterogeneously expressed in a proportion of clinical cases but the significance of this to ER activity is unknown. Significant heterogeneity in the transcriptional activation of ER regulated genes was observed within tumours. This differential activation of the ER cistrome aligned with expression of two known transcriptional co--regulatory factors of ER (FOXA1 and PGR). To examine the degree of heterogeneity for other important phenotypic traits, we used an unsupervised clustering approach to identify cellular sub--populations with diverse cancer associated transcriptional properties, such as: proliferation; hypoxia; and treatment resistance. In particular, we show that we can identify two distinct sub--populations of cells that may have de-novo resistance to endocrine therapies in a treatment naïve PDX model of ER+ breast cancer. One of these consists of cells with a non--proliferative transcriptional phenotype that is enriched for transcriptional properties of ERBB2 tumours. The other is heavily enriched for components of the primary cilia. Gene regulatory networks were used to identify transcription factor regulons that are active in each cell, leading us to identify potential transcriptional drivers (such as E2F7, MYB and RFX3) of the cilia associated endocrine resistant cells. This rare subpopulation of cells also has a highly heterogenous mix of intrinsic subtypes highlighting a potential role of intra--tumour subtype heterogeneity in endocrine resistance and metastatic potential. Overall, These results suggest a high degree of ...

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“…Differential Notch signaling induces expression of cell type‐specifying master transcription factors in progenitors. MCCs are specified through a complex multiciliogenesis transcriptional cascade, including E2Fs, multicilin (Mcidas), or GemC1 as well as a set of downstream factors, such as Foxj1, Rfx2/3, Myb, Foxn4, and micro‐RNAs of the miR‐34/449 family (Campbell, Quigley, & Kintner, 2017; Choksi, Lauter, Swoboda, & Roy, 2014; Kyrousi et al, 2015; Ma, Quigley, Omran, & Kintner, 2014; Marcet et al, 2011; Song et al, 2014; Stubbs et al, 2008; Stubbs, Vladar, Axelrod, & Kintner, 2012; Tan et al, 2013; Walentek et al, 2016; Walentek & Quigley, 2017). ISCs are specified by Foxi1, and are subdivided into α‐ and β‐ISCs by expression of Ubp1 in β‐ISCs, which is regulated by Notch signaling as well (Quigley et al, 2011).…”

Section: The Xenopus Embryonic Mucociliary Epidermismentioning

confidence: 99%

Xenopus epidermal and endodermal epithelia as models for mucociliary epithelial evolution, disease, and metaplasia

Walentek

2021

Genesis

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Summary The Xenopus embryonic epidermis is a powerful model to study mucociliary biology, development, and disease. Particularly, the Xenopus system is being used to elucidate signaling pathways, transcription factor functions, and morphogenetic mechanisms regulating cell fate specification, differentiation and cell function. Thereby, Xenopus research has provided significant insights into potential underlying molecular mechanisms for ciliopathies and chronic airway diseases. Recent studies have also established the embryonic epidermis as a model for mucociliary epithelial remodeling, multiciliated cell trans‐differentiation, cilia loss, and mucus secretion. Additionally, the tadpole foregut epithelium is lined by a mucociliary epithelium, which shows remarkable features resembling mammalian airway epithelia, including its endodermal origin and a variable cell type composition along the proximal–distal axis. This review aims to summarize the advantages of the Xenopus epidermis for mucociliary epithelial biology and disease modeling. Furthermore, the potential of the foregut epithelium as novel mucociliary model system is being highlighted. Additional perspectives are presented on how to expand the range of diseases that can be modeled in the frog system, including proton pump inhibitor‐associated pneumonia as well as metaplasia in epithelial cells of the airway and the gastroesophageal region.

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Correction: Foxn4 promotes gene expression required for the formation of multiple motile cilia

Cited by 10 publications

References 0 publications

Forkhead transcription factor FKH-8 is a master regulator of primary cilia in C. elegans

Forkhead transcription factor FKH-8 is a master regulator of primary cilia in C. elegans

Single cell transcriptomics reveals molecular subtype and functional heterogeneity in models of breast cancer

Xenopus epidermal and endodermal epithelia as models for mucociliary epithelial evolution, disease, and metaplasia

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