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Event: 1911

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

FOXJ1 Protein, Decreased

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
FOXJ1 Protein, Decreased

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Cellular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Cell term
multi-ciliated epithelial cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term
lung epithelium

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
forkhead box protein J1 decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Danio rerio Danio rerio High NCBI
Xenopus laevis Xenopus laevis High NCBI
Mus musculus Mus musculus High NCBI
Homo sapiens Homo sapiens High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

The epithelium of the respiratory tract has a powerful defense mechanism against air-borne pollutants due to the combined performance of mucus-producing goblet cells and ciliated cells that are covered with microtubule-based projections, the cilia. In response to various irritants and pathogens mucus is secreted by goblet cells, and cilia sweep mucus upward by coordinated beating motions thus clearing the airways from these substances. The ciliated airway epithelial cells are typically covered by hundreds of motile cilia. Cilia formation is initiated and coordinated by a distinct gene expression program, led by the transcription factor forkhead box J1 (FOXJ1) (Brody et al., 2000; Zhou and Roy, 2015). In addition to the respiratory tract, FOXJ1 is expressed also in the ciliated cells of the reproductive and central nervous systems (Blatt et al., 1999; Hackett et al., 1995; Lim et al., 1997). 

The multiple motile cilia assembly factors MCIDAS and GMNC converge in positive regulation of FOXJ1 (Arbi et al., 2016; Berta et al., 2016; Stubbs et al., 2012), whereas NOTCH signaling, IL-13-or EGF (epidermal growth factor)-triggered signaling antagonize FOXJ1-driven multiciliogenesis (Gerovac and Fregien, 2016; Gerovac et al., 2014; Gomperts et al., 2007; Shaykhiev et al., 2013). Various other factors are involved in multiple motile cilia assembly, including MYB (acts early in multiciliogenesis downstream of MCIDAS), RFX3 (can act as a co-factor for FOXJ1), ULK4 (modulates the expression of FOXJ1), Wnt signaling, etc. (Choksi et al., 2014; Liu et al., 2016; Schmid et al., 2017; Tan et al., 2013). Most of these factors act upstream or parallel to FOXJ1. FOXJ1 appears to be the major factor in multiciliogenesis, whereby its activity is necessary and also sufficient for programming cells to assemble functional motile cilia (Vij et al., 2012).

FOXJ1 is a master regulator of motile ciliogenesis and is essential to program cells to grow motile cilia (Zhou and Roy, 2015). This key event represents the decrease in the levels or absence of FOXJ1 protein in cells of the respiratory tract. The decrease in FOXJ1 levels inhibits ciliogenesis in multiciliated cells of zebrafish and Xenopus (Stubbs et al., 2008). The knockdown of FOXJ1 results in almost complete absence of cilia in mouse epithelial cells (Brody et al., 2000; Chen J. et al., 1998). On the other hand, the overexpression of FOXJ1 rescues cigarette smoke-mediated suppression of cilia growth in human airway epithelium (Brekman et al., 2014). 

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

FOXJ1 protein levels can be measured by Western blot analysis (Brekman et al., 2014; Didon et al., 2013a; Gomperts et al., 2007; Jacquet et al., 2009; Milara et al., 2012), immunofluorescence (Arbi et al., 2016; Gomperts et al., 2007; Valencia-Gattas et al., 2016) or immunohistochemistry (Abedalthagafi et al., 2016; Danielian et al., 2007; Gao et al., 2015). FOXJ1 protein amounts can be inferred from FOXJ1 mRNA levels that can be measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) (Arbi et al., 2016; Brekman et al., 2014; Didon et al., 2013a; Jacquet et al., 2009; Milara et al., 2012; Stubbs et al., 2012), in situ hybridization (Hackett et al., 1995; Stubbs et al., 2012), and Northern blot analysis (Hackett et al., 1995). In addition, FOXJ1 protein activity can be inferred from FOXJ1 target gene expression levels or from reporter gene expression levels (e.g. luciferase assay) of genes harboring FOXJ1 transcription factor binding sites (Brekman et al., 2014; Lim et al., 1997).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

FOXJ1 is functionally conserved throughout diverse groups of metazoans including flatworm Schmidtea mediterranea, zebrafish Danio rerio, African clawed frog Xenopus laevis (Stubbs et al., 2008; Vij et al., 2012; Yu et al., 2008). Ectopic expression of FOXJ1 triggers ciliogenesis in zebrafish and frog (Stubbs et al., 2008; Yu et al., 2008). Overexpression of FOXJ1 transcription factor in the neural tube of a chick induces cilia formation (Cruz C. et al., 2010). There are multiple studies of FOXJ1 in mice and in human cells (Boon et al., 2014; Brekman et al., 2014; Brody et al., 2000; Chen et al., 1998; Choksi et al., 2014). Furthermore, the target genes of FOXJ1, for example RFX3, are regulated by FOXJ1 across different species (Alten et al., 2012; Didon et al., 2013a).

FOXJ1 function is important for all life stages from embryo through adulthood (Choksi et al., 2014; Stauber et al., 2017). 

FOXJ1 is expressed in the airways of both males and females. In addition to respiratory tract and brain, FOXJ1 is functionally important also in male and female reproductive tissues (Hackett et al., 1995). 

Evidence for Perturbation by Stressor

Cigarette smoke

Whole cigarette smoke exposure or treatment with cigarette smoke extract of normal human bronchial epithelial cells significantly lowered FoxJ1 mRNA and protein levels (Milara et al., 2012; Brekman et al., 2014; Valencia-Gattas et al., 2016; Ishikawa and Ito, 2017). Cigarette smoke extract treatment of normal human bronchial epithelial cells also reduced the expression of cilia-related transcription factor genes, including FOXJ1, RFX2, and RFX3, as well as that of cilia motility and structural integrity genes regulated by FOXJ1, including DNAI1, DNAH5, DNAH9, DNAH10, DNAH11, and SPAG6 (Brekman et al., 2014).

Irradiation

Irradiation causes excessive levels of free radicals and associated lipid peroxidation, damage to DNA, proteins, leading to wide-spread cellular damage (Azzam et al., 2012; Koc et al., 2003; Rodrigues-Moreira et al., 2017; Shirazi et al., 2013). Thoracic irradiation reduces FOXJ1 mRNA levels in mouse lungs (Bernard et al., 2012).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Alten, L., Schuster-Gossler, K., Beckers, A., Groos, S., Ulmer, B., Hegermann, J., et al. (2012). Differential regulation of node formation, nodal ciliogenesis and cilia positioning by Noto and Foxj1. Development 139, 1276-1284.

Arbi, M., Pefani, D.E., Kyrousi, C., Lalioti, M.E., Kalogeropoulou, A., Papanastasiou, A.D., et al. (2016). GemC1 controls multiciliogenesis in the airway epithelium. EMBO Rep. 17, 400-413.

Azzam, E.I., Jay-Gerin, J.P. and Pain, D. (2012). Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett. 327, 48-60.

Bernard, M.E., Kim, H., Rajagopalan, M.S., Stone, B., Salimi, U., Rwigema, J.C., et al. (2012). Repopulation of the irradiation damaged lung with bone marrow-derived cells. In Vivo. 26, 9-18.

Berta, T., Gabriele, P., Sandra, S.-B., Gabriel, G.-G., A, Y.S., Stephan-Otto, A.C., et al. (2016). GEMC1 is a critical regulator of multiciliated cell differentiation. EMBO J. 35, 942-960.

Blatt, E.N., Yan, X.H., Wuerffel, M.K., Hamilos, D.L. and Brody, S.L. (1999). Forkhead transcription factor HFH-4 expression is temporally related to ciliogenesis. Am. J. Respir. Cell Mol. Biol. 21, 168-176.

Boon, M., Wallmeier, J., Ma, L., Loges, N.T., Jaspers, M., Olbrich, H., et al. (2014). MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat. Commun. 5, 4418.

Brekman, A., Walters, M.S., Tilley, A.E. and Crystal, R.G. (2014). FOXJ1 prevents cilia growth inhibition by cigarette smoke in human airway epithelium in vitro. Am. J. Respir. Cell Mol. Biol. 51, 688-700.

Brody, S.L., Yan, X.H., Wuerffel, M.K., Song, S.K. and Shapiro, S.D. (2000). Ciliogenesis and left-right axis defects in forkhead factor HFH-4-null mice. Am. J. Respir. Cell Mol. Biol. 23, 45-51.

Chen, J., Knowles, H.J., Hebert, J.L. and Hackett, B.P. (1998). Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry. J. Clin. Invest. 102, 1077-1082.

Choksi, S.P., Lauter, G., Swoboda, P. and Roy, S. (2014). Switching on cilia: transcriptional networks regulating ciliogenesis. Development 141, 1427-1441.

Cruz, C., Ribes, V., Kutejova, E., Cayuso, J., Lawson, V., Norris, D., et al. (2010). Foxj1 regulates floor plate cilia architecture and modifies the response of cells to sonic hedgehog signalling. Development 137, 4271-4282.

Didon, L., Zwick, R.K., Chao, I.W., Walters, M.S., Wang, R., Hackett, N.R., et al. (2013). RFX3 Modulation of FOXJ1 regulation of cilia genes in the human airway epithelium. Respir. Res. 14, 70-70.

Gerovac, B.J. and Fregien, N.L. (2016). IL-13 inhibits multicilin expression and ciliogenesis via janus kinase/signal transducer and activator of transcription independently of Notch cleavage. Am. J. Respir. Cell Mol. Biol. 54, 554-561.

Gerovac, B.J., Valencia, M., Baumlin, N., Salathe, M., Conner, G.E. and Fregien, N.L. (2014). Submersion and hypoxia inhibit ciliated cell differentiation in a notch-dependent manner. Am. J. Respir. Cell Mol. Biol. 51(4), 516-525.

Gomperts, B.N., Gong-Cooper, X. and Hackett, B.P. (2004). Foxj1 regulates basal body anchoring to the cytoskeleton of ciliated pulmonary epithelial cells. J. Cell Sci. 117, 1329-1337.

Gomperts, B.N., Kim, L.J., Flaherty, S.A. and Hackett, B.P. (2007). IL-13 Regulates Cilia Loss and foxj1 Expression in Human Airway Epithelium. Am. J. Respir. Cell Mol. Biol. 37, 339-346.

Hackett, B.P., Brody, S.L., Liang, M., Zeitz, I.D., Bruns, L.A. and Gitlin, J.D. (1995). Primary structure of hepatocyte nuclear factor/forkhead homologue 4 and characterization of gene expression in the developing respiratory and reproductive epithelium. Proc. Natl. Acad. Sci. U. S. A. 92, 4249-4253.

Ishikawa, S. and Ito, S. (2017). Repeated whole cigarette smoke exposure alters cell differentiation and augments secretion of inflammatory mediators in air-liquid interface three-dimensional co-culture model of human bronchial tissue. Toxicol. in Vitro 38, 170-178.

Koc, M., Taysi, S., Buyukokuroglu, M.E. and Bakan, N. (2003). Melatonin protects rat liver against irradiation-induced oxidative injury. J. Radiat. Res. 44, 211-215.

Lim, L., Zhou, H. and Costa, R.H. (1997). The winged helix transcription factor HFH-4 is expressed during choroid plexus epithelial development in the mouse embryo. Proc. Natl. Acad. Sci. U. S. A. 94, 3094-3099.

Liu, M., Guan, Z., Shen, Q., Lalor, P., Fitzgerald, U., O'brien, T., et al., 2016. Ulk4 Is essential for ciliogenesis and CSF flow. J. Neurosci. 36, 7589-7600.

Milara, J., Armengot, M., Bañuls, P., Tenor, H., Beume, R., Artigues, E., et al. (2012). Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro. Brit. J. Pharmacol. 166, 2243-2262.

Polosa, R., Emma, R., Cibella, F., Caruso, M., Conte, G., Benfatto, F., et al. (2021). Impact of exclusive e-cigarettes and heated tobacco products use on muco-ciliary clearance. Ther. Adv. Chronic Dis. 12, 20406223211035267-20406223211035267. 

Rodrigues-Moreira, S., Moreno, S.G., Ghinatti, G., Lewandowski, D., Hoffschir, F., Ferri, F., et al. (2017). Low-Dose Irradiation Promotes Persistent Oxidative Stress and Decreases Self-Renewal in Hematopoietic Stem Cells. Cell Rep. 20, 3199-3211.

Schmid, A., Sailland, J., Novak, L., Baumlin, N., Fregien, N. and Salathe, M. (2017). Modulation of Wnt signaling is essential for the differentiation of ciliated epithelial cells in human airways. FEBS Lett. 591, 3493-3506.

Shaykhiev, R., Zuo, W.L., Chao, I., Fukui, T., Witover, B., Brekman, A., et al. (2013). EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype. Proc. Natl. Acad. Sci. U. S. A. 110, 12102-12107.

Shirazi, A., Mihandoost, E., Ghobadi, G., Mohseni, M. and Ghazi-Khansari, M. (2013). Evaluation of radio-protective effect of melatonin on whole body irradiation induced liver tissue damage. Cell J. 14, 292-297.

Stauber, M., Weidemann, M., Dittrich-Breiholz, O., Lobschat, K., Alten, L., Mai, M., et al. (2017). Identification of FOXJ1 effectors during ciliogenesis in the foetal respiratory epithelium and embryonic left-right organiser of the mouse. Dev. Biol. 423, 170-188.

Stubbs, J.L., Vladar, E.K., Axelrod, J.D. and Kintner, C. (2012). Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation. Nat. Cell Biol. 14, 140-147.

Tan, F.E., Vladar, E.K., Ma, L., Fuentealba, L.C., Hoh, R., Espinoza, F.H., et al. (2013). Myb promotes centriole amplification and later steps of the multiciliogenesis program. Development 140, 4277-4286.

Valencia-Gattas, M., Conner, G.E. and Fregien, N.L. (2016). Gefitinib, an EGFR Tyrosine Kinase inhibitor, Prevents Smoke-Mediated Ciliated Airway Epithelial Cell Loss and Promotes Their Recovery. PloS ONE 11, e0160216.

Vij, S., Rink, J.C., Ho, H.K., Babu, D., Eitel, M., Narasimhan, V., et al. (2012). Evolutionarily ancient association of the FoxJ1 transcription factor with the motile ciliogenic program. PLoS Genet. 8, e1003019.

Yu, X., Ng, C.P., Habacher, H. and Roy, S. (2008). Foxj1 transcription factors are master regulators of the motile ciliogenic program. Nat. Genet. 40, 1445-1453.

Zhou, F. and Roy, S. (2015). SnapShot: Motile Cilia. Cell 162, 224-224 e221.