Regulation of gene transcription and keratinocyte differentiation by anandamide

Anandamide (AEA) is a member of an endogenous class of lipid mediators, known as endocannabinoids, which are involved in various biological processes. In particular, AEA regulates cell growth, differentiation, and death. Accumulating evidence demonstrates that AEA controls also epidermal differentiation, one of the best characterized mechanisms of cell specialization. Indeed, the epidermis is a keratinized multistratified epithelium that functions as a barrier to protect the organism from dehydration, mechanical trauma, and microbial insults. Its function is established during embryogenesis and is maintained during the whole life span of the organism, through a complex and tightly controlled program, termed epidermal terminal differentiation (or cornification). Whereas the morphological changes that occur during cornification have been extensively studied, the molecular mechanisms that underlie this process remain poorly understood. In this chapter, we summarize current knowledge about the molecular regulation of proliferation and terminal differentiation in mammalian epidermis. In this context, we show that endocannabinoids are finely regulated by, and can interfere with, the differentiation program. In addition, we review the role of AEA in the control of cornification, and show that it occurs by maintaining a transcriptional repression of gene expression through increased DNA methylation.