皇家华人

We've asked Rhian Walther from the Pichaud Lab to tell us about her recent publication in Journal of Cell Science:

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Studying how epithelial cell-cell contacts are formed so that these cells can assemble into organs has been a longstanding interest of mine. 听Many proteins are required to form these cell-cell contacts, called Zonula Adherens (ZA). 听These past years, my work has been to unpick this complexity and identify mechanisms of ZA morphogenesis. 听I have been lucky to identify so far two distinct mechanisms that are crucial for ZA formation. 听The first involves the exclusion of PAR3 from the PAR complex and apical membrane. Apical exclusion of PAR3 determines the position of the ZA and the separation of junctional proteins from the apical membrane of the cell. In parallel, I鈥檝e also discovered that at the developing ZA, a retention mechanism exists for PAR3 that prevents PAR3 from spreading to the lateral cell membrane. This is important because when this retention mechanism is disabled, apical membrane can invade the lateral membrane. 听At the same time, a student in the lab, Mubarik Burki, was working on the small GTPase Rap1. 听We quickly noticed that the pak4 and Rap1 loss of function phenotypes had a lot in common. This prompted us to investigate Rap1 function in epithelial polarity in more detail.

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Nearly a decade ago, a former post-doc in the lab, Noelia Pinal performed a screen to identify regulators of small GTPases that might play a role in epithelial cell morphogenesis. 听Using photoreceptors as a model epithelial cell, Noelia identified the dizzy gene as being required for epithelial cell patterning. 听However, at that time we were unable to describe this interesting observation in more precise molecular terms. 听Later, as part of her PhD work, Mubarik found that Rap1, the GTPase regulated by dizzy, is required to properly form the ZA. 听Unfortunately, her PhD drew to a close before she could really establish how exactly Rap1 might function during this process and how this function might relate to that of Pak4 and PAR3. This is where I stepped in and designed experiments to clarify the relationship between Rap1, Pak4 and PAR3 during epithelial polarity and ZA morphogenesis.

I was able to show that the function of Rap1 is linked to that of pak4, and provided evidence that these two factors synergize in stabilizing E-cadherin (the main adhesion molecule at the ZA), and regulate the interface between E-cadherin and PAR3, thus promoting PAR3 retention. Our current model is that Rap1 and Pak4 regulate the interface between E-cadherin and its binding partner beta-catenin () and that Rap1 regulates E-cadherin stability both via promoting Pak4 localization at the ZA and linking the E-cadherin-beta-catenin module to the underlying F-actin cytoskeleton.

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Epithelial cells are the most widely present cell type in our body. 听They frequently act as a barrier between the organism and the outside environment. The ability of epithelial cells to form and maintain their cell-cell contacts is required for organ development and maintenance of tissue integrity. 听The inability to form cell-cell contacts can lead to organ failure. 听Further, many cancers originate from epithelial cells, and the loss of epithelial cell-cell contacts is frequently associated with the development of cancer. 听Understanding the links between how cells form and regulate their contacts can help provide insight into the pathology of this disease. 听听

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Epithelial cell junctions could be thought of performing a similar role to the joins that hold together fencing panels. 听If these joins are placed at random or if they aren鈥檛 screwed in tightly, the fence won鈥檛 be strong enough to stay standing for long. 听

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Our work confirms that formation of cell-cell contacts is indeed a complicated process! 听With respect to ZA retention, while we have identified key components, it appears that they do not function as part of simple, linear networks. 听Untangling the molecular mechanisms that underpin the interdependency between these proteins remains a key challenge. 听

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Link to Rhian's publication .

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