Chloride channels regulate differentiation and barrier functions of the mammalian airway
- University of California, San Francisco, United States
- Chan Zuckerberg Biohub, United States
- Yale University School of Medicine, United States
Abstract
The conducting airway forms a protective mucosal barrier and is the primary target of airway disorders. The molecular events required for the formation and function of the airway mucosal barrier, as well as the mechanisms by which barrier dysfunction leads to early onset airway diseases, remain unclear. In this study, we systematically characterized the developmental landscape of the mouse airway using single-cell RNA sequencing and identified remarkably conserved cellular programs operating during human fetal development. We demonstrated that in mouse, genetic inactivation of chloride channel Ano1/Tmem16a compromises airway barrier function, results in early signs of inflammation, and alters the airway cellular landscape by depleting epithelial progenitors. Mouse Ano1-/- mutants exhibited mucus obstruction and abnormal mucociliary clearance that resemble the airway defects associated with cystic fibrosis. The data reveal critical and non-redundant roles for Ano1 in organogenesis, and show that chloride channels are essential for mammalian airway formation and function.
Data availability
Sequencing reads and processed data in the format of gene-cell count tables are available from the Sequence Read Archive (SRA) (SRA accession: PRJNA548516).
-
trachea developmentNCBI Bioproject, PRJNA548516.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (RO1 NS069229)
- Lily Yeh Jan
Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD089639)
- Mu He
Howard Hughes Medical Institute
- Yuh Nung Jan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, He 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
-
- 2,975
- views
-
- 462
- downloads
-
- 27
- 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)
Chloride channels regulate differentiation and barrier functions of the mammalian airway
eLife 9:e53085.
https://doi.org/10.7554/eLife.53085
Further reading
-
- Developmental Biology
- Evolutionary Biology
The insect brain and the timing of its development underwent evolutionary adaptations. However, little is known about the underlying developmental processes. The central complex of the brain is an excellent model to understand neural development and divergence. It is produced in large parts by type II neuroblasts, which produce intermediate progenitors, another type of cycling precursor, to increase their neural progeny. Type II neuroblasts lineages are believed to be conserved among insects, but little is known on their molecular characteristics in insects other than flies. Tribolium castaneum has emerged as a model for brain development and evolution. However, type II neuroblasts have so far not been studied in this beetle. We created a fluorescent enhancer trap marking expression of Tc-fez/earmuff, a key marker for intermediate progenitors. Using combinatorial labeling of further markers, including Tc-pointed, we characterized embryonic type II neuroblast lineages. Intriguingly, we found nine lineages per hemisphere in the Tribolium embryo while Drosophila produces only eight per brain hemisphere. These embryonic lineages are significantly larger in Tribolium than they are in Drosophila and contain more intermediate progenitors. Finally, we mapped these lineages to the domains of head patterning genes. Notably, Tc-otd is absent from all type II neuroblasts and intermediate progenitors, whereas Tc-six3 marks an anterior subset of the type II lineages. Tc-six4 specifically marks the territory where anterior-medial type II neuroblasts differentiate. In conclusion, we identified a conserved pattern of gene expression in holometabolan central complex forming type II neuroblast lineages, and conserved head patterning genes emerged as new candidates for conferring spatial identity to individual lineages. The higher number and greater lineage size of the embryonic type II neuroblasts in the beetle correlate with a previously described embryonic phase of central complex formation. These findings stipulate further research on the link between stem cell activity and temporal and structural differences in central complex development.
-
- Cell Biology
- Developmental Biology
Disease-causing mutations in the signaling protein BMP4 impair its secretion, but only when it is made as a homodimer.
