ABSTRACT
Desmosomes are intercellular junctions of epithelia and are of widespread importance in the maintenance of tissue architecture. We provide evidence that desmosomal adhesion has a function in epithelial morphogenesis and cell-type-specific positioning. Blocking peptides corresponding to the cell adhesion recognition (CAR) sites of desmosomal cadherins block alveolar morphogenesis by epithelial cells from mammary lumen. Desmosomal CAR-site peptides also disrupt positional sorting of luminal and myoepithelial cells in aggregates formed by the reassociation of isolated cells. We demonstrate that desmosomal cadherins and E-cadherin are comparably involved in epithelial morphoregulation. The results indicate a wider role for desmosomal adhesion in morphogenesis than has previously been considered.
Subject(s)
Cadherins/physiology , Cell Adhesion/physiology , Cytoskeletal Proteins/physiology , Desmosomes/physiology , Epithelial Cells/cytology , Epithelial Cells/physiology , Animals , Binding Sites , Breast/cytology , Cadherins/chemistry , Cadherins/genetics , Cattle , Cell Aggregation , Cell Culture Techniques/methods , Cell Line , Cell Size , Cells, Cultured , Cytoskeletal Proteins/chemistry , Desmoplakins , Female , Gene Expression Regulation , Humans , Integrins/analysis , Integrins/physiology , Mammary Glands, Animal/cytology , Mice , Morphogenesis , Pulmonary Alveoli/cytology , Reverse Transcriptase Polymerase Chain Reaction , Transcription, GeneticABSTRACT
Members of the armadillo protein gene family, which includes plakoglobin and beta-catenin, have important functions in cytoskeleton/cell membrane interactions. These proteins may act as linker molecules at adherens junctions and desmosomes at the plasma membrane; in addition, they may have pivotal roles in signal transduction pathways and significant effects on cell behaviour during development. Here, we describe the first human mutations in one of these dual function proteins, plakophilin 1 (band-6 protein; refs 8-10). The affected individual has a complete absence of immunostaining for plakophilin 1 in the skin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the plakophilin 1 gene (PKP1). Clinically, there are features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin are small and poorly formed with widening of keratinocyte intercellular spaces and perturbed desmosome/keratin intermediate filament interactions. The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell-call adhesion and epidermal morphogenesis.
