Desmosomes, membrane structures which form mechanical links between adjacent cells and thus contribute to tissue integrity, are composed of three basic protein families; desmosomal cadherins, armadillo proteins and plakins. Currently, my work focuses upon the desmosomal cadherins.  Divided into two categories, desmogleins and desmocollins, these molecules bind their counterparts extending from desmosomes on adjacent cells.  An interesting attribute of desmosomal cadherins is their differential expression between organs and often within organs,
  most strikingly illustrated in the epidermis where all three desmogleins are present but reside at different positions with respect to the basal and corneal layers. The unequal distribution of desmosomal cadherins raises several intriguing questions. Why do various tissues and tissue components utilize different cadherins if cadherins merely provide a mechanical link between two cells? The answer could lie in a differential ability to mediate the adhesive interaction, however, several lines of evidence suggest that individual desmogleins and desmocollins may have specific roles in tissue differentiation and morphogenesis. Current work in our lab demonstrates that knocking down desmoglein1, for example, in organotypic cultures mimicking the three dimensional histology of epidermis results in an inability of human keratinocytes to stratify and differentiate. In addition, clinical evidence revealing the pathological impact of the autoimmune diseases pemphigus foliaceous and pemphigus vulgaris, as well as a bacterial blistering disease called scalded skin syndrome, all of which involve disruption of specific desmosomal cadherins, corroborates the hypothesis that individual cadherins carry out unique functions beyond their capacity for mediating cell-cell adhesion.

I am pursuing several projects at the moment designed to identify and characterize novel desmoglein binding partners with the ultimate goal being to provide a mechanistic explanation for differential desmoglein/desmocollin expression with regard to differentiation and morphogenesis. In addition, to build upon existing, qualitative data pertaining to the contribution of these cadherins to cell-cell adhesion strength, I am developing biomimetic surfaces displaying functional cadherin ectodomains, a tool which should allow us to quantitatively describe desmosomal adhesion with respect to desmogleins, desmocollins and associated desmosomal components.

 
previous next