Abstract
ABSTRACTThe airways are lined by secretory and multiciliated cells which function together to remove particles and debris from the respiratory tract. The transcriptome of multiciliated cells has been extensively studied, but the function of many of the genes identified is unknown. We have established an assay to test the ability of over-expressed transcripts to promote multiciliated cell differentiation in mouse embryonic tracheal explants. Overexpression data indicated that Fibronectin type 3 and ankyrin repeat domains 1 (Fank1) and JAZF zinc finger 1 (Jazf1) promoted multiciliated cell differentiation alone, and cooperatively with the canonical multiciliated cell transcription factor Foxj1. Moreover, knock-down of Fank1 or Jazf1 in adult mouse airway epithelial cultures demonstrated that these factors are both required for ciliated cell differentiation in vitro. This analysis identifies Fank1 and Jazf1 as novel regulators of multiciliated cell differentiation. Moreover, we show that they are likely to function downstream of IL6 signalling and upstream of Foxj1 activity in the process of ciliated cell differentiation. In addition, our in vitro explant assay provides a convenient method for preliminary investigation of over-expression phenotypes in the developing mouse airways.This article has an associated First Person interview with the first author of the paper.
Highlights
The airway mucociliary escalator consists of secretory and multicilated cells and captures inhaled debris and particles for clearance
Gene Ontology (GO) analysis confirmed that the FOXJ1-GFP transcriptome was enriched in ciliated cell-specific gene classes compared to the whole genome (Fig. 1B)
Of the three factors that promoted ciliated cell fate we focused on Fank1 and JAZF zinc finger 1 (Jazf1). (The Homeodomain interacting protein kinase 1 (Hipk1) cDNA was inconveniently large and did not electroporate efficiently in the assay.) Fank1 and Jazf1 promoted ciliated cell fate to a similar extent to Foxj1 and we wondered if the three factors could act synergistically
Summary
The airway mucociliary escalator consists of secretory and multicilated cells and captures inhaled debris and particles for clearance. It is essential for respiratory health and changes in its cellular composition or function can cause respiratory conditions, including chronic infections which can lead to more serious, irreversible, airway disease such as bronchiectasis. A decrease in the number of ciliated cells, or changes in ciliary beat frequency, are characteristics of Primary Ciliary Dyskinesia (Fliegauf et al, 2007; Tilley et al, 2015).
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