Decreased Skin Barrier Lipid Acylceramide and Differentiation-Dependent Gene Expression in Ichthyosis Gene Nipal4-Knockout Mice

NIPAL4 is one of the causative genes for autosomal recessive congenital ichthyosis. However, the role of NIPAL4 in skin barrier formation and the molecular mechanism of ichthyosis pathology caused by NIPAL4 mutations, have not yet been determined. Here, we found that Nipal4-knockout (KO) mice exhibited neonatal lethality due to skin barrier defects. Histological analyses showed several morphological abnormalities in the Nipal4-KO epidermis, including impairment of lipid multilayer structure formation, hyperkeratosis, immature keratohyalin granules, and developed heterochromatin structures. The levels of the skin barrier lipid acylceramide were decreased in Nipal4-KO mice. Expression of genes involved in skin barrier formation normally increases during keratinocyte differentiation, in which chromatin remodeling is involved. However, the induction of Krtl, Lor, Flg, ElovIl, and Dgat2 was impaired in Nipal4-KO mice. NIPAL4 is a putative Mg2+ transporter, and Mg2+ concentration in differentiated keratinocytes of Nipal4-KO mice was indeed lower than that of wild-type mice. Our results suggest that low Mg2+ concentration causes aberration in the proper chromatin remodeling process, which in turn leads to failure of differentiation-dependent gene induction in keratinocytes. Our findings provide insights into Mg2+-dependent regulation of gene expression and skin barrier formation during keratinocyte differentiation.