Role of the basement membrane proteins nidogen-1 and -2 in skin physiology and pathology

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The cutaneous basement membrane (BM), which separates the epidermal and dermal compartments, is a highly complex structure providing both an adhesive substrate and a dynamic interface, thus governing the overall structural integrity of the skin. It acts as a barrier that restricts the passage of molecules between epidermis and dermis, but permits the passage of migrating cells under physiological and pathological conditions. Further, BMs and their components are regulators of cellular activities, such as growth, differentiation, migration, and they influence tissue development and repair. The nidogens, nidogen-1 and -2, are related, ubiquitous BM proteins which have been considered to play a key role in BM assembly and stabilization. However, deletion of either of the NID genes in the mouse results in only mild changes with no alteration of tissue or BM architecture indicating partial redundancy within the family. Indeed, mice deficient for both nidogen isoforms die shortly after birth showing a range of abnormalities which could be directly assigned to BM defects. Surprisingly, in some organs ultrastructurally normal BM were found indicating tissue specific functions for nidogens in BMs. Although the nidogen double null mice show partial redundancy for the two nidogens wound healing studies and tumor invasion experiments in either nidogen-1 or -2 deficient mice provide evidence for isoform specific functions. Therefore the main goal of this project will be to gain more insight into the isoform specific functions in skin physiology and pathology and to analyse the mechanisms underlying these differences.