PhD student - Deciphering the systems that control epithelial cellpolarity (1.0 FTE)

Employer
Utrecht University
Location
Netherlands
Posted
June 30 2017
Position Type
Full Time
Organization Type
Academia

Background


Cell polarity is a fundamental property that is essential in human development and for the functioning of adult tissues. Epithelial cells, the most common polarized cells, depend on polarization into apical and basolateral domains to act as selectively permeable barriers between body compartments and with the outside environment. Loss of polarity in epithelial cells contributes to diseases like polycystic kidney disease and retinal dystrophies. Moreover, epithelial cancers are characterized by loss of cell polarity and epithelial integrity, and many polarity regulators are mutated or deregulated in cancer.



The molecular mechanisms that control the formation and maintenance of distinct polarized domains are still far from understood. We also know little of the causal mechanisms by which deregulation of polarity contributes to tumorigenesis. The research in this Vici project focuses on two questions:


  1. what is the network of interactions between polarity determinants that maintains polarity in established epithelia, and

  2. what are the direct consequences of disrupting cell polarity on epithelial integrity, morphology, and cell fate.

To address these questions, the candidate will combine precisely controlled perturbations of the polarizing system with accurate characterization of the effects of these perturbations on the polarizing machinery and on epithelial organization and cell fate.


Approach


The studies will make use of the nematode C. elegans as a model system, because this animal is ideal for in vivo studies of polarity. Due to its transparency and limited number of cells, polarity can be followed in the context of a developing animal with single cell resolution. The presence of multiple distinct types of epithelia allows the investigation of the polarizing machinery in different contexts. Finally, recent developments in inducible protein degradation and tissue-specific gene knockouts make it possible to inactivate proteins in a time- and tissue-controlled manner, and follow the effects on cell polarity, morphology, and fate over time.



Within the Vici framework, multiple individual projects will be developed with input from the candidates. Technical approaches used include the use of CRISPR/Cas9 to engineer fluorescently tagged polarity regulators, and to engineer proteins that can be inactivated in a time- and tissue-controlled manner, live cell imaging using advanced light microscopy, and the use of RNAseq to investigate the effects of polarity loss on cell fate.



This job comes from a partnership with Science Magazine and Euraxess