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Title: Functional RNAi analysis of novel regulators of adhesion with further characterisation of the role of LZTFL1 in keratinocytes and heart disease
Author: Bruche, Susann
ISNI:       0000 0004 6061 4434
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Adherens junctions mediate intercellular adhesion in most tissues. Cell-cell contacts need to be regulated in a variety of biological processes including developmental morphogenesis, wound healing and transendothelial migration. Actin remodelling is crucial for adherens junction control and members of the family of Rho small GTPases are key regulators of adherens junction formation, maintenance and turnover. Although only a few Rho GTPases have been show to date to control adherens junctions, they govern a large number of cellular processes downstream of cadherin interaction by activating different effector proteins. Considering the complexity of adherens junction biology, a complex network of actin-binding proteins and Rho GTPase effectors are likely to mediate adherens junction assembly and preservation. Therefore, we performed RNAi screens and identified several actin-binding proteins and Rho GTPase effectors as novel adherens junction regulators. Here, I validate the role of several of these proteins during adherens junction assembly and further investigate the mechanisms involved for a few of them. Skin and heart are under constant mechanical stress and therefore require specialised cell-cell contacts to ensure tissue integrity. In addition to adherens junctions, epithelial cells and cardiomyocytes possess desmosomes and both complexes warrant junction stability. In this study, I identify LZTFL1 as a protein involved in the stabilisation of cell-cell contacts. LZTFL1 is a tumour suppressor and is involved in trafficking towards cilia. Here I show that LZTFL1 depletion negatively affects adherens junction-associated E-cadherin and actin as well as desmosome-coupled desmoplakin and keratin 14. I further demonstrate that LZTFL1 can bind to α-catenin and keratin 14 and thus might be able to mediate crosstalk between different cell-cell contact complexes. In cardiovascular disease, contraction and mechanical coupling of neighbouring cardiomyocytes need to adapt to changes in pressure and volume load. In accordance with its cell-cell contact-stabilising function in epithelial cells, I detect changes in LZTFL1 expression levels in different cardiac pathologies. These changes are specific to certain pathologies and disease stages and likely represent adaptations to altered mechanical requirements of the heart.
Supervisor: Braga, Vania ; Rueckert, Daniel ; Russo, Alessandra Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral