Project Details
Projekt
Coupling intercellular adhesion, polarity and mechanical signals at epidermal junctions
Applicant
Professorin Dr. Sandra Iden
Subject Area
Cell Biology
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 273723548
Cell polarization is essential for proper development, tissue homeostasis and regeneration. Studies in lower organisms identified important regulators of cell and tissue architecture. Polarity proteins of the Par3-aPKC-Par6 complex mediate diverse cellular processes and couple control of cell shape to signalling pathways regulating growth, cell fate and differentiation. Yet, how these conserved polarity regulators contribute to mammalian tissue function and disease is much less clear. The skin is a tensile tissue constantly exposed to mechanical stress. Whether and how polarity proteins drive polarization in stratified epithelia like the skin epidermis and how they contribute to chemical and mechanical signalling in this tissue is largely unknown. Our recent work revealed important roles of Par3 and aPKCl in skin cancer, with junction-localized but not cytoplasmic Par3 promoting growth, survival and ultimately tumorigenesis. We further showed that Par3 inactivation in the mouse epidermis results in epidermal barrier defects, stem cell decline and premature differentiation. Moreover, Par3 controls P-cadherin surface expression, thereby regulating epidermal cell-cell interactions. Within the SPP1782 we combined different biophysical methods with cell biological, genetic and proteinbiochemical approaches to reveal unexpected mechanisms through which junctional Par3 couples mechanical signals at intercellular adhesions with cellular responses to ensure epidermal homeostasis and barrier integrity. We deciphered that Par3 promotes Rho-driven actomyosin contractility to foster intrinsic force generation at cell-cell contacts, important to maintain the tight junctional barrier. Moreover, our data indicate that polarity proteins mediate dynamic junction remodelling in response to external mechanical cues. Intriguingly, correcting myosin activation was also sufficient to rescue mitotic defects and ectopic differentiation upon Par3 loss, unravelling a central role of actomyosin regulation in polarity protein-dependent epidermal self-renewal and differentiation. Having established the importance of junctional Par3 for keratinocyte mechanics, key efforts in the second funding period will aim to unravel further molecular links between mechanical and polarity signalling at intercellular adhesions that mediate cytoskeletal and biochemical responses. We will use gain- and loss-of-function approaches, proteomics, biophysical and imaging methods to examine the relevance of three classes of adhesion molecules that are deregulated following Par3 loss. Moreover, we will investigate mechanochemical effector pathways downstream of junctional polarity proteins and ask how polarity networks transmit mechanical cues to the cell’s interior to instruct strain adaptation. Together, this SPP1782 project will provide molecular insight into the coupling of intercellular junctions, cell polarity and force transmission in an important barrier-forming epithelium.
DFG Programme
Priority Programmes
