To identify genes that are essential for the functions of cells and organs, 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 the skin by analyzing mice with an epidermis-specific Ahed deficiency. Those mice have apoptotic cells in their epidermis from the perinatal stage. Thereafter, they develop skin barrier disruptions over time, which cause lethality soon after birth. Experiments using 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 is a nuclear protein, we further revealed that AHED interacts with known spliceosomal proteins in HeLa cells. Moreover, altered splicing mRNA patterns were demonstrated in Ahed deficient keratinocytes. These results suggest that AHED plays a crucial role in the maintenance of epidermal integrity, and more importantly, it contributes to mRNA splicing that is essential for multiple cell lineages.