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, while 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 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.

Embryonic AP1 Transcription Factor Deficiency Causes a Collodion Baby-Like Phenotype

“…Consistent with such a role, we observe a marked shift of loricrin from the cytoplasmic to nuclear compartment in AP1 factor inactivated epidermis of E13.5, E15.5 and E17.5 mice and in cultured cells derived from these mice. This fits with our previous findings showing nuclear loricrin localization in the epidermis of adult TAM67-expressing epidermis (Rorke et al, 2015a; Rorke et al, 2015b). It is interesting that wild-type loricrin moves to the nucleus in the epidermal cells of these AP1 factor perturbed mice (Rorke et al, 2015a; Rorke et al, 2015b).…”

“…3D). This is also observed in TAM67-positive adult mouse epidermis (Rorke et al, 2015b; Rorke et al, 2015a). Fig.…”

“…Similar to adult epidermis (Rorke et al, 2015b; Rorke et al, 2015a), TAM67-FLAG localizes in the nucleus of suprabasal epidermal keratinocytes in doxycycline-treated TAM67-rTA embryos (Fig. 3A).…”

“…AP1 factors in the epidermis are expressed in a differentiation-dependent manner (Welter and Eckert, 1995) and control expression of differentiation associated genes (Crish et al, 1998; Crish et al, 2006), including filaggrin (Jang et al, 1996). We recently described a phenotype in adult mice that includes epidermal hyperproliferation, parakeratosis, hyperkeratosis, impaired barrier function, nuclear loricrin accumulation and reduced filaggrin level in response to suprabasal epidermis-specific inactivation of activator protein 1 (AP1) transcription factor function (Rorke et al, 2010; Rorke et al, 2015a; Rorke et al, 2015b). In addition, we observe nuclear loricrin accumulation and, in some animals, constricting bands (pseudoainhum) encircle the tail and digits (Rorke et al, 2015b).…”

Loss of epidermal AP1 transcription factor function reduces filaggrin level, alters chemokine expression and produces an ichthyosis-related phenotype

“…9, 10, 27, 55, 56 Inactivation of AP1 factor function in the suprabasal epidermis of TAM67-rTA mice results in a phenotype that includes features of ichthyosis vulgaris (altered epidermal differentiation, reduced filaggrin content) 57 and loricrin keratoderma (pseudoainhum, nuclear loricrin accumulation). 58, 59 A possible model of phenotype development is present in Figure 5e.…”