To provide a stable environmental barrier, the epidermis requires an integrated network of cytoskeletal elements and cellular junctions. Nevertheless, the epidermis ranks among the body’s most dynamic tissues, continually regenerating itself and responding to cutaneous insults. As keratinocytes journey from the basal compartment towards the cornified layers, they completely reorganize their adhesive junctions and cytoskeleton. These architectural components are more than just rivets and scaffolds — they are active participants in epidermal morphogenesis that regulate epidermal polarization, signalling and barrier formation.

Desmosomes are highly specialized anchoring junctions that link intermediate filaments to sites of intercellular adhesion, thus facilitating the formation of a supracellular scaffolding that distributes mechanical forces throughout a tissue. These junctions are thus particularly important for maintaining the integrity of tissues that endure physical stress, such as the epidermis and myocardium. The importance of the classic mechanical functions of desmosomal constituents is underscored by pathologies reported in animal models and an ever-expanding list of human mutations that target both desmosomal cadherins and their associated cytoskeletal anchoring proteins. However, the notion that desmosomes are static structures that exist simply to glue cells together belies their susceptibility to remodeling in response to environmental cues and their important tissue-specific roles in cell behavior and signaling. Here, we review the molecular blueprint of the desmosome and models for assembling its protein components to form an adhesive interface and the desmosomal plaque. We also discuss emerging evidence of supra-adhesive roles for desmosomal proteins in regulating tissue morphogenesis and homeostasis. Finally, we highlight the dynamic nature of these adhesive organelles, examining mechanisms in health and disease for modulating adhesive strength and stability of desmosomes.

Dsg1 (desmoglein 1) is a member of the cadherin family of Ca2+-dependent cell adhesion molecules that is first expressed in the epidermis as keratinocytes transit out of the basal layer and becomes concentrated in the uppermost cell layers of this stratified epithelium. In this study, we show that Dsg1 is not only required for maintaining epidermal tissue integrity in the superficial layers but also supports keratinocyte differentiation and suprabasal morphogenesis. Dsg1 lacking N-terminal ectodomain residues required for adhesion remained capable of promoting keratinocyte differentiation. Moreover, this capability did not depend on cytodomain interactions with the armadillo protein plakoglobin or coexpression of its companion suprabasal cadherin, Dsc1 (desmocollin 1). Instead, Dsg1 was required for suppression of epidermal growth factor receptor–Erk1/2 (extracellular signal-regulated kinase 1/2) signaling, thereby facilitating keratinocyte progression through a terminal differentiation program. In addition to serving as a rigid anchor between adjacent cells, this study implicates desmosomal cadherins as key components of a signaling axis governing epithelial morphogenesis.

Mitochondria form interconnected networks that dynamically remodel in response to cellular needs. Using live-cell imaging, we investigate the role of the actin cytoskeleton in regulating mitochondrial fission and fusion. We identify cycling of actin filaments onto and off of subsets of cellular mitochondria. The association of actin filaments with mitochondrial subpopulations is transient; actin quickly disassembles, then reassembles around a distinct subpopulation, efficiently cycling through all cellular mitochondria within 14 min. The focal assembly of actin induces local, Drp1-dependent fragmentation of the mitochondrial network. On actin disassembly, fragmented mitochondria undergo rapid fusion, leading to regional recovery of the tubular mitochondrial network. Cycling requires dynamic actin polymerization and is blocked by inhibitors of both Arp2/3 and formins. We propose that cyclic assembly of actin onto mitochondria modulates the fission/fusion balance, promotes network remodelling and content mixing, and thus may serve as an essential mechanism regulating mitochondrial network homeostasis.

Genetic disorders of the Ras/MAPK pathway, termed RASopathies, produce numerous abnormalities, including cutaneous keratodermas. The desmosomal cadherin, desmoglein-1 (DSG1), promotes keratinocyte differentiation by attenuating MAPK/ERK signaling and is linked to striate palmoplantar keratoderma (SPPK). This raises the possibility that cutaneous defects associated with SPPK and RASopathies share certain molecular faults. To identify intermediates responsible for executing the inhibition of ERK by DSG1, we conducted a yeast 2-hybrid screen. The screen revealed that Erbin (also known as ERBB2IP), a known ERK regulator, binds DSG1. Erbin silencing disrupted keratinocyte differentiation in culture, mimicking aspects of DSG1 deficiency. Furthermore, ERK inhibition and the induction of differentiation markers by DSG1 required both Erbin and DSG1 domains that participate in binding Erbin. Erbin blocks ERK signaling by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2, a protein genetically linked to the RASopathy, Noonan-like syndrome with loose anagen hair (NS/LAH). DSG1 overexpression enhanced this inhibitory function, increasing Erbin-SHOC2 interactions and decreasing Ras-SHOC2 interactions. Conversely, analysis of epidermis from DSG1-deficient patients with SPPK demonstrated increased Ras-SHOC2 colocalization and decreased Erbin-SHOC2 colocalization, offering a possible explanation for the observed epidermal defects. These findings suggest a mechanism by which DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation.

The heterochromatic domains of Drosophila melanogaster (pericentric heterochromatin, telomeres, and the fourth chromosome) are characterized by histone hypoacetylation, high levels of histone H3 methylated on lysine 9 (H3-mK9), and association with heterochromatin protein 1 (HP1). While the specific interaction of HP1 with both H3-mK9 and histone methyltransferases suggests a mechanism for the maintenance of heterochromatin, it leaves open the question of how heterochromatin formation is targeted to specific domains. Expression characteristics of reporter transgenes inserted at different sites in the fourth chromosome define a minimum of three euchromatic and three heterochromatic domains, interspersed. Here we searched for cis-acting DNA sequence determinants that specify heterochromatic domains. Genetic screens for a switch in phenotype demonstrate that local deletions or duplications of 5 to 80 kb of DNA flanking a transposon reporter can lead to the loss or acquisition of variegation, pointing to short-range cis-acting determinants for silencing. This silencing is dependent on HP1. A switch in transgene expression correlates with a switch in chromatin structure, judged by nuclease accessibility. Mapping data implicate the 1360 transposon as a target for heterochromatin formation. We propose that heterochromatin formation is initiated at dispersed repetitive elements along the fourth chromosome and spreads for ϳ10 kb or until encountering competition from a euchromatic determinant.The chromosomes of higher eukaryotes are organized into multiple domains with distinct properties. The partitioning of chromosomes into zones of condensed heterochromatin and dispersed euchromatin is readily seen in interphase nuclei. Heterochromatin has the property of silencing most genes that are normally packaged in euchromatin; this silencing is strikingly evident where euchromatic genes are abnormally juxtaposed to heterochromatic domains by chromosome rearrangement or transposition, resulting in position-effect variegation (PEV) (16). Work with multiple systems has led to a model of heterochromatin formation based on a specific combination of biochemical marks. Heterochromatic regions are characterized by histone hypoacetylation and methylation of histone H3 at lysine 9 (producing H3-mK9), in most cases accompanied by binding of heterochromatin protein 1 (HP1) and in some cases associated with methylation of the DNA (31). In Drosophila melanogaster, mutations in HP1 [Su(var)2-5] and in an H3-K9 methyltransferase [Su(var)3-9] cause a loss of heterochromatin-induced silencing. A remarkable property of heterochromatin is the ability to spread in cis in response to the loss of boundary constraints or to changes in the dosage or activity of chromatin components (24,38). The interaction of HP1 with both the modified histone H3-mK9 and the modifying enzyme SU(VAR)3-9 suggests a plausible model for the maintenance and spreading of heterochromatin (reviewed in reference 16).

Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation, disruption of which may drive carcinogenesis. The epigenetic regulator () is one of the most frequently mutated genes in all cancers, particularly epithelial cancers, yet its normal function in these tissues is unknown. Here, we identify a novel role for KMT2D in coordinating this fine balance, as depletion of KMT2D from undifferentiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification. Genome-wide, KMT2D interacts with p63 and is enriched at its target enhancers. Depletion of KMT2D results in a broad loss of enhancer histone modifications H3 Lys 4 (H3K4) monomethylation (H3K4me1) and H3K27 acetylation (H3K27ac) as well as reduced expression of p63 target genes, including key genes involved in epithelial development and adhesion. Together, these results reveal a critical role for KMT2D in the control of epithelial enhancers and p63 target gene expression, including the requirement of KMT2D for the maintenance of epithelial progenitor gene expression and the coordination of proper terminal differentiation.

Symmetric cell division requires the even partitioning of genetic information and cytoplasmic contents between daughter cells. While the mechanisms coordinating the segregation of the genome are well known, the processes which ensure organelle segregation between daughter cells remain less well-understood 1 . Here, we identify multiple actin assemblies that play distinct but complementary roles in mitochondrial organization and inheritance in mitosis. First, we find a dense meshwork of subcortical actin cables assembled throughout the mitotic cytoplasm. This network scaffolds the endoplasmic reticulum and organizes three-dimensional mitochondrial positioning to ensure the equal segregation of mitochondrial mass at cytokinesis. Second, we identify a dynamic wave of actin filaments reversibly assembling on the surface of mitochondria through mitosis. Mitochondria sampled by this wave are enveloped within actin clouds that can spontaneously break symmetry to form elongated comet tails. Mitochondrial comet tails promote randomly directed bursts of movement that shuffle mitochondrial position within the mother cell to randomize inheritance of healthy and damaged mitochondria between daughter cells. Thus, parallel mechanisms mediated by the actin cytoskeleton ensure both equal and random inheritance of mitochondria in symmetrically dividing cells.