Canonical Notch signaling in the developing lung is required for determination of arterial smooth muscle cells and selection of Clara versus ciliated cell fate

Abstract

SummaryLung development is the result of complex interactions between four tissues: epithelium, mesenchyme, mesothelium and endothelium. We marked the lineages experiencing Notch1 activation in these four cellular compartments during lung development and complemented this analysis by comparing the cell fate choices made in the absence of RBPj, the essential DNA binding partner of all Notch receptors. In the mesenchyme, RBPj was required for the recruitment and specification of arterial vascular smooth muscle cells (vSMC) and for regulating mesothelial epithelial-mesenchymal transition (EMT), but no adverse affects were observed in mice lacking mesenchymal RBPj. We provide indirect evidence that this is due to vSMC rescue by endothelial-mesenchymal transition (EnMT). In the epithelium, we show that Notch1 activation was most probably induced by Foxj1-expressing cells, which suggests that Notch1-mediated lateral inhibition regulates the selection of Clara cells at the expense of ciliated cells. Unexpectedly, and in contrast to Pofut1-null epithelium, Hes1 expression was only marginally reduced in RBPj-null epithelium, with a corresponding minimal effect on pulmonary neuroendocrine cell fate selection. Collectively, the primary roles for canonical Notch signaling in lung development are in selection of Clara cell fate and in vSMC recruitment. These analyses suggest that the impact of ␥-secretase inhibitors on branching in vitro reflect a non-cell autonomous contribution from endothelial or vSMC-derived signals.

Notch2 Is Required for Inflammatory Cytokine-Driven Goblet Cell Metaplasia in the Lung

“…Notch activation leads to a series of cleavage events, culminating in the generation of the Notch intracellular domain (NICD), which translocates to the nucleus, where it interacts with a transcription factor complex to regulate gene expression. The role of Notch signaling in regulating cell-fate decisions during development and repair has been studied in many contexts, including in mucociliary tissues (Deblandre et al, 1999;Guseh et al, 2009;Morimoto et al, 2010Morimoto et al, , 2012Rock et al, 2011;Tsao et al, 2009). In the epidermis of the Xenopus embryo, activation of Notch suppresses the ciliated cell fate, whereas inhibition of Notch signaling results in an overproduction of ciliated cells (Deblandre et al, 1999).…”

MicroRNA-449 in cell fate determination

“…79,80 Finally, notch signaling is required for the differentiation of epithelial cells from progenitors into diverse cells in the bronchial epithelium. [81][82][83] This partially happens through direct cell-cell interaction, by a mechanism referred to as "lateral inhibition," meaning that a cell adopting a particular fate can keep its neighboring cells from doing so. The transmembrane proteins Notch and Delta are well-defined mediators of this connecting cilia of the eye, the sensory stereocilia of the inner ear, or the renal or pancreatic cilia.…”

Three cheers for the goblet cell: maintaining homeostasis in mucosal epithelia

“…Complementary studies with loss of Notch signaling in pulmonary epithelium result in a loss of secretory club (Clara) cells, with a concomitant increase in ciliated cells [62,63]. In the eye, loss of canonical Notch signaling results in a failure of goblet cell formation during eye development and the loss of pre-existing conjunctival goblet cells in the adult [48] ( Figure 4A).…”