Abstract
Clara cells (CCs) are a morphologically and operationally heterogeneous population of Secretoglobin Scgb1a1-expressing secretory cells that are crucial for airway homeostasis and post-injury repair. Analysis of the extent and origin of CC diversity are limited by knowledge of genes expressed in these cells and their precursors. To identify novel putative markers of CCs and explore the origins of CC diversity, we characterized global changes in gene expression in embryonic lungs in which CCs do not form due to conditional disruption of Notch signaling (RbpjkCNULL). Microarray profiling, Real Time PCR (qRT-PCR), and RNA in situ hybridization (ISH) identified eleven genes downregulated in the E18.5 airways of Rbpjkcnull compared to controls, nearly half not previously known to mark CCs. ISH revealed that several genes had overlapping but distinct domains of expression of in the normal developing lung (E18.5). Notably, Reg3g, Chad, Gabrp and Lrrc26 were enriched in proximal airways, Hp in the distal airways and Upk3a in clusters of cells surrounding Neuroepithelial Bodies (NEBs). Seven of the eleven genes, including Reg3g, Hp, and Upk3a, were expressed in the adult lung in CCs in a pattern similar to that observed in the developing airways. qRT-PCR-based analysis of gene expression of CCs isolated from different airway regions of B1-EGFP reporter mice corroborated the spatial enrichment in gene expression observed by ISH. Our study identifies candidate markers for CC-precursors and CCs and supports the idea that the diversification of the CC phenotype occurs already during embryonic development.
Highlights
Secretory cells are among the most abundant cell type in the mammalian airways
Transcriptional Profiling of E18.5 Lungs from Notch-deficient RbpjkCNULL Mice Identifies Genes Enriched in Clara cells (CCs)
This is true for CCs, the most abundant and functionally diverse secretory cells of the murine lung
Summary
Secretory cells are among the most abundant cell type in the mammalian airways. These cells produce a variety of secretory products, including mucus, that are key regulators of the airway inflammation and homeostasis [1]. Secretory cells are known to be heterogeneous in their morphology, molecular composition and responses to environmental challenge. This heterogeneity is observed across species and correlates with position of cells along the proximal-distal (P-D) axis of the airway epithelium [1,2]. Scgb1a1 is expressed in secretory cells in the mouse lung but, unlike in humans, Scgb1a1+ secretory cells in mice (hereafter referred to as CCs) are the predominant secretory cell type in this species. We focus on the development and diversification of CCs in the mouse lung
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