UC San Diego

The epidermis is a continually regenerating tissue, which requires a tightly regulated balance between stem/ progenitor cell proliferation and differentiation. As epidermal stem/progenitor cells enter the differentiation pathway they initiate the expression of differentiation genes and cease proliferation. The balance between proliferation and differentiation is traditionally studied at the transcription factor level, however the stem/ progenitor cell microenvironment also plays a pivotal role in regulating cell fate decisions. A natural gradient of E -cadherin mediated adhesion exists within the epidermis such that increasing adhesion correlates with the progression of differentiation. Epidermal deletion of the cell-cell adhesion protein, E-cadherin, results in delayed progression of epidermal differentiation. Therefore, E- cadherin mediated adhesion may function as a microenvironmental cue to promote epidermal differentiation. Using a transgenic mouse model with uniform E-cadherin stabilization throughout the epidermis we demonstrate that E-cadherin is sufficient to both induce epidermal differentiation and inhibit proliferation. In cultured primary mouse epidermal stem cells, E-cadherin stabilization at the plasma membrane is both necessary and sufficient to promote differentiation and inhibit proliferation. Transcriptional profiling shows that E-cadherin mediates a portion of transcriptional changes that occur during differentiation. The mechanism of E-cadherin mediated differentiation is determined to be a cooperative effort between the binding of E-cadherin to [beta]-catenin and p120. Altogether, this work provides mechanistic insight into E-cadherin mediated signal transduction and represents a fundamental advancement in understanding how intercellular adhesion proteins influence cell fate decisions