The development of the mammalian epidermis is a highly complex multistage process that involves a sequence of steps from epidermal specification to expansion and development of derivative appendages, e.g., hair follicles [
1,
2]. For the precise regulation of epidermal development, several signaling pathways are involved closely regulating the spatiotemporal coordination of cellular proliferation, differentiation, and tightly controlled cell death [
1,
3,
4]. Epidermal development has become a model to study developmental mesenchymal-epithelial interactions between epidermis and dermis, the specific mechanisms of embryonic wound healing without scarring and cellular mechanisms in rapidly proliferating and self-renewing tissues [
1‐
4].
The two AAA+ (ATPases associated with various cellular activities) superfamily proteins Ruvbl1 (Pontin, Tip48) and Ruvbl2 (Reptin, Tip49) have their central roles in promoting cell proliferation and cell survival. They contribute to various cellular processes including chromatin remodeling (Tip60, Ino80, and Scrap) as well as DNA damage signaling and repair [
5‐
13]. Ruvbl1 is, e.g., required for the assembly and function of multiple protein complexes including the Tip60 complex regulating the tumor suppressor protein p53 [
8,
13,
14]. In addition, the Ruvbl proteins or protein complexes involving the Ruvbl proteins modulate transcriptional activity of, e.g., pro-proliferative factors like MYC and ß-catenin and play important roles in multiple steps of cell cycle progression and cellular metabolism [
6,
8,
13]. We recently identified Ruvbl1 as a component of ciliary protein complexes in renal tubular, bronchial, and ependymal epithelial cells [
15]. Ruvbl1 also seems to be essential for early embryogenesis in mice [
15,
16], and it has been suggested that loss of murine stem cell populations may be due to apoptosis [
16]. To study the significance of Ruvbl1 in rapidly proliferating and differentiating mammalian tissue in vivo, we generated a targeted knockout of
Ruvbl1 in murine epidermal cells. Here, we show that the embryonic loss of
Ruvbl1 in mouse epidermis leads to severe developmental defects, resulting in loss of skin architecture and skin barrier defects associated with perinatal death.