Epithelial cells have a characteristic apicobasal polarity, which is necessary for their function as barriers between different extracellular environments ( Drubin and Nelson, 1996 Mostov et al., 2000). In order to function effectively, the alveolar surface must form a selectively permeable monolayer where cell-cell contact provides important spatial cues that are required to generate cell polarity/communications ( Nelson, 2003a Nelson, 2003b Boitano et al., 2004).Ĭell polarity, the asymmetry in distribution of cellular constituents within a single cell, is fundamental to cellular functions and essential for generating cell diversity. These buds undergo stereotypic rounds of branching and outgrowth to give rise to a tree-like respiratory organ, which contains different specialized epithelial cell types organized along the proximodistal axis ( Cardoso, 2000 Warburton et al., 2000 Warburton, 2008 Metzger et al., 2008). Mammalian lung development begins when two primary buds consisting of an inner epithelial layer surrounded by mesenchyme, arise from the laryngotracheal groove in the ventral foregut. The correct functioning of lung epithelium is essential to life. These findings uncover novel functions for Eya1 as a crucial regulator of the complex behavior of distal embryonic lung epithelium. Indeed, genetic activation of Notch partially rescues Eya1 −/− lung epithelial defects. As Notch signaling promotes progenitor cell identity at the expense of differentiated cell phenotypes, we test whether genetic activation of Notch could rescue the Eya1 −/− lung phenotype, which is characterized by loss of epithelial progenitors, increased epithelial differentiation but reduced branching. In addition, in Eya1 −/− lungs, perpendicular division is not maintained and Numb is segregated to both daughter cells in mitotic epithelial cells, leading to inactivation of Notch signaling. Thus, epithelial cell polarity and mitotic spindle orientation are defective after interfering with Eya1 function in vivo or in vitro. Hence, Eya1 promotes both perpendicular division as well as Numb asymmetric segregation to one daughter in mitotic distal lung epithelium, probably by controlling aPKCζ phosphorylation. We further show that Eya1 protein regulates cell polarity, spindle orientation and the localization of Numb, which inhibits Notch signaling. Interfering with the function of these proteins in vitro randomizes spindle orientation and changes cell fate. Consistent with these findings, spindle orientation-regulatory proteins Insc, LGN (Gpsm2) and NuMA, and the cell fate determinant Numb are asymmetrically localized in embryonic lung distal epithelium. Herein, we provide the first evidence that embryonic lung distal epithelium is polarized with characteristic perpendicular cell divisions. Today is highlighted.Cell polarity, mitotic spindle orientation and asymmetric division play a crucial role in the self-renewal/differentiation of epithelial cells, yet little is known about these processes and the molecular programs that control them in embryonic lung distal epithelium. Dates are based on the Gregorian calendar. Time is adjusted for DST when applicable. * All times are local time for California City. Business Date to Date (exclude holidays).
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