Keratinocyte-Specific Ablation of RIPK4 Allows Epidermal Cornification but Impairs Skin Barrier Formation

Abstract

In humans, receptor-interacting protein kinase 4 (RIPK4) mutations can lead to the autosomal recessive Bartsocas-Papas and popliteal pterygium syndromes, which are characterized by severe skin defects, pterygia, as well as clefting. We show here that the epithelial fusions observed in RIPK4 full knockout (KO) mice are E-cadherin dependent, as keratinocyte-specific deletion of E-cadherin in RIPK4 full KO mice rescued the tail-to-body fusion and fusion of oral epithelia. To elucidate RIPK4 function in epidermal differentiation and development, we generated epidermis-specific RIPK4 KO mice (RIPK4). In contrast to RIPK4 full KO epidermis, RIPK4 epidermis was normally stratified and the outside-in skin barrier in RIPK4 mice was largely intact at the trunk, in contrast to the skin covering the head and the outer end of the extremities. However, RIPK4 mice die shortly after birth due to excessive water loss because of loss of tight junction protein claudin-1 localization at the cell membrane, which results in tight junction leakiness. In contrast, mice with keratinocyte-specific RIPK4 deletion during adult life remain viable. Furthermore, our data indicate that epidermis-specific deletion of RIPK4 results in delayed keratinization and stratum corneum maturation and altered lipid organization and is thus indispensable during embryonic development for the formation of a functional inside-out epidermal barrier.

Stem cell membrane-coated isotretinoin for acne treatment

“…However, the mechanism by which the stem cell membrane interacts in this process still needs to be further explored. The tight junction and LC layer, as the two main barriers of transdermal delivery, are believed to interact with each other and alter lipid organization [33]. Based on our findings, we hypothesize that the LC layer, tight junction, and endocytosis all play an important part in the mechanism of transdermal delivery and can interact with each other (Fig.…”

Stem cell membrane-coated isotretinoin for acne treatment

“…However, the mechanism by which the stem cell membrane interacts in this process still needs to be further explored. The tight junction and LC layer, as the two main barriers of transdermal delivery, are believed to interact with each other and alter lipid organization [36]. Based on our ndings, we hypothesize that the LC layer, tight junction, and endocytosis all play an important part in the mechanism of transdermal delivery and can interact with each other (Figure 9).…”

Insight Into the Function of RIPK4 in Keratinocyte Differentiation and Carcinogenesis

“…Previous studies have indicated that RIPK4 can modulate the actin cytoskeleton and restrict intercellular adhesion (6). Skin-specific loss of RIPK4 results in delayed keratinization, stratum corneum maturation, and aberrantly lipid distribution (7). Therefore, RIPK4 is essential for keratinocyte differentiation and the formation of a normal epidermal barrier (6).…”