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Epidermal keratinocytes undergo a unique form of terminal differentiation and programmed cell death known as cornification. Cornification leads to the formation of the outermost skin barrier, i.e. the cornified layer, as well as to the formation of hair and nails. Different genes are expressed in coordinated waves to provide the structural and regulatory components of cornification. Differentiation-associated keratin intermediate filaments form a complex scaffold accumulating in the cytoplasm and, upon removal of cell organelles, fill the entire cell interior mainly to provide mechanical strength. In addition, a defined set of proteins is cross-linked by transglutamination in the cell periphery to form the so-called cornified envelope. Extracellular modifications include degradation of the tight linkages between corneocytes by excreted proteases, which allows corneocyte shedding by desquamation, and stacking and modification of the excreted lipids that fill the intercellular spaces between corneocytes to provide a water-repellant barrier. In hard skin appendages such as hair and nails these tight intercorneocyte connections remain permanent. Various lines of evidence exist for a role of organelle disintegration, proteases, nucleases, and transglutaminases contributing to the actual cell death event. However, many mechanistic aspects of kearatinocyte death during cornification remain elusive. Importantly, it has recently become clear that keratinocytes activate anti-apoptotic and anti-necroptotic pathways to prevent premature cell death during terminal differentiation. This review gives an overview of the current concept of cornification as a mode of programmed cell death and the anti-cell death mechanisms in the epidermis that secure epidermal homeostasis. This article is part of a Special Section entitled: Cell Death Pathways.

The evolution of amniotes has involved major molecular innovations in the epidermis. In particular, distinct structural proteins that undergo covalent cross-linking during cornification of keratinocytes facilitate the formation of mechanically resilient superficial cell layers and help to limit water loss to the environment. Special modes of cornification generate amniote-specific skin appendages such as claws, feathers, and hair. In mammals, many protein substrates of cornification are encoded by a cluster of genes, termed the epidermal differentiation complex (EDC). To provide a basis for hypotheses about the evolution of cornification proteins, we screened for homologs of the EDC in non-mammalian vertebrates. By comparative genomics, de novo gene prediction and gene expression analyses, we show that, in contrast to fish and amphibians, the chicken and the green anole lizard have EDC homologs comprising genes that are specifically expressed in the epidermis and in skin appendages. Our data suggest that an important component of the cornified protein envelope of mammalian keratinocytes, that is, loricrin, has originated in a common ancestor of modern amniotes, perhaps during the acquisition of a fully terrestrial lifestyle. Moreover, we provide evidence that the sauropsid-specific beta-keratins have evolved as a subclass of EDC genes. Based on the comprehensive characterization of the arrangement, exon–intron structures and conserved sequence elements of EDC genes, we propose new scenarios for the evolutionary origin of epidermal barrier proteins via fusion of neighboring S100A and peptidoglycan recognition protein genes, subsequent loss of exons and highly divergent sequence evolution.

Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity1–4. Sparse taxon sampling has previously been proposed to confound phylogenetic inference5, and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families—including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species.