ABSTRACT
Correction to: NPG Asia Materials (2018) https://doi.org/10.1038/s41427-018-0014-9 published online on 16 April 2018.
ABSTRACT
Several mutant mice have been generated to model connexin (Cx)-linked skin diseases; however, the role of connexins in skin maintenance and during wound healing remains to be fully elucidated. Here we generated a novel, viable, and fertile mouse (Cx26CK14-S17F/+) with the keratitis-ichthyosis-deafness mutant (Cx26S17F) driven by the cytokeratin 14 promoter. This mutant mouse mirrors several Cx26-linked human skin pathologies suggesting that the etiology of Cx26-linked skin disease indeed stems from epidermal expression of the Cx26 mutant. Cx26CK14-S17F/+ foot pad epidermis formed severe palmoplantar keratoderma, which expressed elevated levels of Cx26 and filaggrin. Primary keratinocytes isolated from Cx26CK14-S17F/+ neonates exhibited reduced gap junctional intercellular communication and migration. Furthermore, Cx26CK14-S17F/+ mouse skin wound closure was normal but repaired epidermis appeared hyperplastic with elevated expression of cytokeratin 6. Taken together, we suggest that the Cx26S17F mutant disturbs keratinocyte differentiation and epidermal remodeling following wound closure. We further posit that Cx26 contributes to epidermal homeostasis by regulating keratinocyte differentiation, and that mice harboring a disease-linked Cx26 mutant display epidermal abnormalities yet retain most wound healing properties.
Subject(s)
Connexins/genetics , Deafness/genetics , Epidermis/metabolism , Ichthyosis/genetics , Keratoderma, Palmoplantar/genetics , Wound Healing/genetics , Animals , Cell Differentiation , Connexin 26 , Connexins/metabolism , Deafness/metabolism , Deafness/pathology , Disease Models, Animal , Epidermis/pathology , Female , Filaggrin Proteins , Founder Effect , Gap Junctions/metabolism , Gap Junctions/pathology , Gene Expression , Humans , Ichthyosis/metabolism , Ichthyosis/pathology , Intermediate Filament Proteins/genetics , Intermediate Filament Proteins/metabolism , Keratin-14/genetics , Keratin-14/metabolism , Keratinocytes/metabolism , Keratinocytes/pathology , Keratoderma, Palmoplantar/metabolism , Keratoderma, Palmoplantar/pathology , Male , Mice , Mice, Transgenic , Mutation , Primary Cell Culture , Promoter Regions, GeneticABSTRACT
At present, it is unclear if melanocytes contain Cx43 gap junctions and whether Cx43 expression is regulated in melanoma onset and progression. To this end, we cultured pure populations of mouse melanocytes and found that they had no detectable Cx43 and exhibited an inability for dye transfer indicating they were devoid of functional gap junctions. Given the evidence that melanomas acquire the expression of other connexin isoforms during tumor progression, we assessed if Cx43 was also expressed and assembled into gap junctions at any stage of human melanoma onset and progression to distant metastases. Nearly all primary melanomas within the epidermis lacked Cx43. In contrast, nodal metastases expressed low levels of Cx43 which was markedly higher in distant metastases that had invaded vital organs. Importantly, in all stages of melanoma progression, Cx43 could be detected in intracellular compartments but was rarely assembled into gap junctions indicative of functional gap junction channels. Overall, these studies suggest that melanocytes do not form Cx43 homocellular gap junctions and even though Cx43 levels increase during melanoma progression, this connexin rarely assembles into gap junction structures.