A newly identified spliceosomal protein Ahed is essential for homeostasis of the epidermis

Abstract

Abstract To identify genes that are essential for cellular and organ functions, we established a homozygous mutant mouse embryonic stem cell bank from which we identified a gene, named Attenuated Hematopoietic Development (Ahed), that plays an essential role in hematopoiesis. Here we characterize the role of Ahed in skin development by analyzing mice with an epidermis-specific Ahed deficiency (EcKO). Those mice have increased numbers of apoptotic cells in the epidermis from the fetal stage. Thereafter, Ahed-EcKO mice develop skin barrier disruptions over time, which cause lethality soon after birth, showing epidermal abnormalities including the loss of filaggrin and an increase of pro-inflammatory gene expression. Experiments using Tam/ERT2-mediated inducible Ahed deletion in vivo and in vitro revealed that an Ahed deficiency leads to keratinocyte apoptosis, impairs keratinocyte proliferation and promotes dermatitis development. Since we found that Ahed has a critical role in hematopoiesis as a spliceosomal protein that controls gene splicing of hematopoiesis-related molecules, we further characterized the protein interactions of Ahed with other spliceosomal proteins in HeLa cells, and identified the altered splicing of mRNAs in Ahed-deficient keratinocytes. These results suggest that Ahed plays an indispensable role in processing mRNAs during development and in maintaining skin integrity, and more importantly, it contributes to mRNA splicing that is essential for multiple cell lineages.