Deletion of K1/K10 does not impair epidermal stratification but affects desmosomal structure and nuclear integrity

Abstract

SummaryKeratins K1 and K10 are the most abundant proteins in the upper epidermis where they polymerize to form intermediate filaments (IFs). In addition to their well-established function in providing epidermal stability, K1/K10 (i.e. the dimer between K1 and K10) IFs are supposed to be important for terminal epidermal differentiation and barrier formation. It was previously shown that the imbalanced deletion of one of the partner keratins, K10, disturbed epidermal homoeostasis, although stability was provided by compensatory upregulation of K5/K14, which formed IFs together with the remaining K1. Here, we show that deletion of both partner keratins, K1 and K10, results in lethal postnatal skin fragility in mice. Krt1 2/2 ;Krt10 2/2 mice revealed that K1/K10 IFs are unexpectedly dispensable for epidermal stratification. Although the stratum corneum was less compact and cornified envelope differentiation was impaired, a dye exclusion assay showed that the development of a functional water barrier was surprisingly independent from the presence of K1/K10 IFs. The deletion of K1/K10 was not compensated by any other keratin pair such as the basal epidermal keratins K5/K14, and electron microscopy revealed total absence of IFs in the suprabasal epidermis. Although plakoglobin was unchanged, the expression of the desmosomal proteins desmoplakin, desmocollin 1 and desmoglein 1 were altered and suprabasal desmosomes were smaller in Krt1 2/2 ;Krt10 2/2 than in wild-type epidermis suggesting an involvement of K1/K10 IFs in desmosome dynamics. Furthermore, Krt1 2/2 ;Krt10 2/2 mice showed premature loss of nuclei during epidermal differentiation and lower levels of emerin, lamin A/C and Sun1, revealing a previously unknown function for IFs in maintaining nuclear integrity in the upper epidermis.

Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18

“…This is also in agreement with the recently described phenotype of Krt1/10 doubly deficient mice (Wallace et al, 2012).…”

“…3D). Possibly, the biotin assay performed in Krt1/10-doubly-deficient mice may not fully reveal the barrier state of these mice (Wallace et al, 2012). Furthermore, the number of intact cornified envelopes was significantly reduced to ,17% in Krt1 2/2 compared to ,84% in Krt1 +/+ and ,55% in Krt10 +/+ mouse skins (Fig.…”

Suppression of epithelial differentiation by Foxi3 is essential for molar crown patterning

“…Keratin 10 (K10) is a type I keratin, which forms intermediate filaments with the type II keratin 1 (K1). In skin, suprabasal cells express K1 and K10 both during embryogenesis and in adulthood (Wallace et al, 2012). qRT-PCR validation showed a downregulation of Notch2 (0.51-fold), K1 (0.32-fold) and K10 (0.16-fold) in the Foxi3 cKO bud stage epithelium (Fig.…”

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…To overcome the latter, mice lacking the entire KtyI and KtyII genes in their epidermis were generated, in addition to mice lacking both KRT1 and KRT10. Such mice developed a fully stratified epidermis but died perinatally because of extensive epidermal damage (Wallace et al 2012;Bar et al 2014;Kumar et al 2015). Most importantly, these mice showed diminished intercellular adhesion and significantly smaller desmosomes.…”