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Suppressing AP1 factor signaling in the suprabasal epidermis produces a keratoderma phenotype.

ABSTRACT: Keratodermas comprise a heterogeneous group of highly debilitating and painful disorders characterized by thickening of the skin with marked hyperkeratosis. Some of these diseases are caused by genetic mutation, whereas other forms are acquired in response to environmental factors. Our understanding of signaling changes that underlie these diseases is limited. In the present study, we describe a keratoderma phenotype in mice in response to suprabasal epidermis-specific inhibition of activator protein 1 transcription factor signaling. These mice develop a severe phenotype characterized by hyperplasia, hyperkeratosis, parakeratosis, and impaired epidermal barrier function. The skin is scaled, constricting bands encircle the tail and digits, the footpads are thickened and scaled, and loricrin staining is markedly reduced in the cornified layers and increased in the nucleus. Features of this phenotype, including nuclear loricrin localization and pseudoainhum (autoamputation), are characteristic of the Vohwinkel syndrome. We confirm that the phenotype develops in a loricrin-null genetic background, indicating that suppressed suprabasal AP1 factor function is sufficient to drive this disease. We also show that the phenotype regresses when suprabasal AP1 factor signaling is restored. Our findings suggest that suppression of AP1 factor signaling in the suprabasal epidermis is a key event in the pathogenesis of keratoderma.

SUBMITTER: Rorke EA

PROVIDER: S-EPMC4268309 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Epidermal keratinocyte differentiation on the body surface is a carefully choreographed process that leads to assembly of a barrier that is essential for life. Perturbation of keratinocyte differentiation leads to disease. Activator protein 1 (AP1) transcription factors are key controllers of this process. We have shown that inhibiting AP1 transcription factor activity in the suprabasal murine epidermis, by expression of dominant-negative c-jun (TAM67), produces a phenotype type that resembles human keratoderma. However, little is understood regarding the structural and molecular changes that drive this phenotype. In the present study we show that TAM67-positive epidermis displays altered cornified envelope, filaggrin-type keratohyalin granule, keratin filament, desmosome formation and lamellar body secretion leading to reduced barrier integrity. To understand the molecular changes underlying this process, we performed proteomic and RNA array analysis. Proteomic study of the corneocyte cross-linked proteome reveals a reduction in incorporation of cutaneous keratins, filaggrin, filaggrin2, late cornified envelope precursor proteins, hair keratins and hair keratin-associated proteins. This is coupled with increased incorporation of desmosome linker, small proline-rich, S100, transglutaminase and inflammation-associated proteins. Incorporation of most cutaneous keratins (Krt1, Krt5 and Krt10) is reduced, but incorporation of hyperproliferation-associated epidermal keratins (Krt6a, Krt6b and Krt16) is increased. RNA array analysis reveals reduced expression of mRNA encoding differentiation-associated cutaneous keratins, hair keratins and associated proteins, late cornified envelope precursors and filaggrin-related proteins; and increased expression of mRNA encoding small proline-rich proteins, protease inhibitors (serpins), S100 proteins, defensins and hyperproliferation-associated keratins. These findings suggest that AP1 factor inactivation in the suprabasal epidermal layers reduces expression of AP1 factor-responsive genes expressed in late differentiation and is associated with a compensatory increase in expression of early differentiation genes.

Project description:BackgroundThe skin is largely comprised of keratinocytes within the interfollicular epidermis. Over approximately two weeks these cells differentiate and traverse the thickness of the skin. The stage of differentiation is therefore reflected in the positions of cells within the tissue, providing a convenient axis along which to study the signaling events that occur in situ during keratinocyte terminal differentiation, over this extended two-week timescale. The canonical ERK-MAPK signaling cascade (Raf-1, MEK-1/2 and ERK-1/2) has been implicated in controlling diverse cellular behaviors, including proliferation and differentiation. While the molecular interactions involved in signal transduction through this cascade have been well characterized in cell culture experiments, our understanding of how this sequence of events unfolds to determine cell fate within a homeostatic tissue environment has not been fully characterized.MethodsWe measured the abundance of total and phosphorylated ERK-MAPK signaling proteins within interfollicular keratinocytes in transverse cross-sections of human epidermis using immunofluorescence microscopy. To investigate these data we developed a mathematical model of the signaling cascade using a normalized-Hill differential equation formalism.ResultsThese data show coordinated variation in the abundance of phosphorylated ERK-MAPK components across the epidermis. Statistical analysis of these data shows that associations between phosphorylated ERK-MAPK components which correspond to canonical molecular interactions are dependent upon spatial position within the epidermis. The model demonstrates that the spatial profile of activation for ERK-MAPK signaling components across the epidermis may be maintained in a cell-autonomous fashion by an underlying spatial gradient in calcium signaling.ConclusionsOur data demonstrate an extended phospho-protein profile of ERK-MAPK signaling cascade components across the epidermis in situ, and statistical associations in these data indicate canonical ERK-MAPK interactions underlie this spatial profile of ERK-MAPK activation. Using mathematical modelling we have demonstrated that spatially varying calcium signaling components across the epidermis may be sufficient to maintain the spatial profile of ERK-MAPK signaling cascade components in a cell-autonomous manner. These findings may have significant implications for the wide range of cancer drugs which therapeutically target ERK-MAPK signaling components.

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Suppressing AP1 factor signaling in the suprabasal epidermis produces a keratoderma phenotype.

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