Abstract
Cell polarity is essential for the architecture and function of numerous epithelial tissues. Here, we show that apical restriction of planar cell polarity (PCP) components is necessary for the maintenance of epithelial integrity. Using the mammalian pancreas as a model, we find that components of the core PCP pathway, such as the transmembrane protein Van Gogh-like (VANGL), become apically restricted over a period of several days. Expansion of VANGL localization to the basolateral membranes of progenitors leads to their death and disruption of the epithelial integrity. VANGL basolateral expansion does not affect apico-basal polarity but acts in the cells where Vangl is mislocalized by reducing Dishevelled and its downstream target ROCK. This reduction in ROCK activity culminates in progenitor cell egression, death, and eventually pancreatic hypoplasia. Thus, precise spatiotemporal modulation of VANGL-dependent PCP signaling is crucial for proper pancreatic morphogenesis.
Highlights
Establishment of polarity is essential for the function of many cell types
By perturbing the localization of VANGL2, we demonstrate that a stringent regulation of the level and localization of this protein at the membrane of progenitors is required to maintain epithelial integrity
We have previously shown that the expression of VANGL1/2 is initiated in the pancreatic epithelium at around E11 when apico-basal polarity is first established[9]
Summary
Establishment of polarity is essential for the function of many cell types. In epithelia two axes of polarity have been characterized: 1) apico-basal polarity orients cells from the free surface or the lumen to the basal lamina and 2) planar polarity coordinates polarization of cell structures or behaviors in the plane of the tissue, orthogonal to the apico-basal axis. The developing pancreas consists of a network of tubes lined by polarized progenitors, the apical membranes of which line the duct lumen[4,5]. As endocrine differentiation is decreased as a result of mutation of CELSR2/3, it suggests PCP components are essential regulators linking pancreas morphogenesis with cell fate[9]. How would these components be localized in a radially symmetric tubular epithelium and what would their function be in in tubular organs remains to be determined. Systematic examination of the localization of other core PCP components reveals a cell-autonomous negative regulation of VANGL on Dishevelled, reinforcing the model of inhibitory intracellular interaction currently proposed in lower vertebrates
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