Keratin 9 Is Required for the Structural Integrity and Terminal Differentiation of the Palmoplantar Epidermis

Abstract

Keratin 9 (K9) is a type I intermediate filament protein whose expression is confined to the suprabasal layers of the palmoplantar epidermis. Although mutations in the K9 gene are known to cause epidermolytic palmoplantar keratoderma, a rare dominant-negative skin disorder, its functional significance is poorly understood. To gain insight into the physical requirement and importance of K9, we generated K9-deficient (Krt9−/−) mice. Here, we report that adult Krt9−/−mice develop calluses marked by hyperpigmentation that are exclusively localized to the stress-bearing footpads. Histological, immunohistochemical, and immunoblot analyses of these regions revealed hyperproliferation, impaired terminal differentiation, and abnormal expression of keratins K5, K14, and K2. Furthermore, the absence of K9 induces the stress-activated keratins K6 and K16. Importantly, mice heterozygous for the K9-null allele (Krt9+/−) show neither an overt nor histological phenotype, demonstrating that one Krt9 allele is sufficient for the developing normal palmoplantar epidermis. Together, our data demonstrate that complete ablation of K9 is not tolerable in vivo and that K9 is required for terminal differentiation and maintaining the mechanical integrity of palmoplantar epidermis.

To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease

“…10 Conditional deletion of Krt9 in a murine model demonstrated that Krt9 is responsible for maintaining mechanical integrity and terminal differentiation of volar skin. 11 These data highlight not only the functional importance of KRT9 for structural support but also the validity of KRT9 as a marker of positional skin identity. KRT9 can be activated by pressure-activating mitogen-activated protein kinases.…”

Factors Determining the Efficiency of Porcine Somatic Cell Nuclear Transfer: Data Analysis with Over 200,000 Reconstructed Embryos

“…Approximately 15% of KO mice have mutations that lead to death (National Human Genome Research Institute, www.genome.gov/12514551). Although some genetic functions in mammals are redundant and the targeted loss of genes sometimes was reported to have no effect ( Joyner et al, 1991), absence of a gene may also impact expression of other genes (Fu et al, 2014). Compared to KOFFs, more live piglets could be obtained with lower incidence of abnormalities.…”

Epidermolytic Palmoplantar Keratoderma of Vörner-Case Report

“…The monogenic nature of EPPK, with mutations almost exclusively in the KRT9 hotspot, and the fact that it is accessible in a localized area, makes this disease an ideal model for therapeutic shortinterfering RNA (siRNA) [9]. Therefore, RNA interference strategies are being investigated as an approach for the genetic silencing of specific alleles for dominant negative keratin diseases [10][11][12][13][14][15].…”

“…It is a rare autosomal dominant genodermatosis, characterized by yellowish and diffuse thickening of the palmar and plantar skin [1,3,7]. It is a unique keratinopathy among keratodermas and the most common diffuse form, usually caused by mutations in keratin (KRT9) and rarely in the keratin 1 gene (KRT1), which is located in chromosome 171 [8,9]. This type of keratin is expressed in suprabasal cells of the epidermis, specifically of palmar and plantar regions [9,10].…”

“…It is a unique keratinopathy among keratodermas and the most common diffuse form, usually caused by mutations in keratin (KRT9) and rarely in the keratin 1 gene (KRT1), which is located in chromosome 171 [8,9]. This type of keratin is expressed in suprabasal cells of the epidermis, specifically of palmar and plantar regions [9,10]. This article reports a rare clinical case of classical EPPK that began in the first months of life with initially bullish characteristics simulating epidermolysis bullosa simplex.…”