Cdc42 Deficiency Leads To Epidermal Barrier Dysfunction by Regulating Intercellular Junctions and Keratinization of Epidermal Cells during Mouse Skin Development

Abstract

Rationale : Cdc42 is a Rho GTPase that regulates diverse cellular functions. Here, we used genetic techniques to investigate the role of Cdc42 in epidermal development and epidermal barrier formation. Methods : Keratinocyte-restricted Cdc42 knockout mice were generated with the Cre-LoxP system under the keratin 14 (K14) promoter. The skin and other tissues were collected from mutant and wild-type mice, and their cellular, molecular, morphological, and physiological features were analyzed. Results : Loss of Cdc42 in the epidermis in vivo resulted in neonatal lethality and impairment of epidermal barrier formation. Cdc42 deficiency led to the loss of epidermal stem cells. The absence of Cdc42 led to increased thickening of the epidermis, which was associated with increased proliferation and reduced apoptosis of keratinocytes. In addition, Cdc42 deficiency damaged tight junctions, adherens junctions and desmosomes. RNA sequencing results showed that the most significantly altered genes were enriched by the terms of “keratinization” and “cornified envelope” (CE). Among the differentially expressed genes in the CE term, several members of the small proline-rich protein (SPRR) family were upregulated. Further study revealed that there may be a Cdc42-SPRR pathway, which may correlate with epidermal barrier function. Conclusions : Our study indicates that Cdc42 is essential for epidermal development and epidermal barrier formation. Defects in Cdc42-SPRR signaling may be associated with skin barrier dysfunction and a variety of skin diseases.

The novel GINS4 axis promotes gastric cancer growth and progression by activating Rac1 and CDC42

“…Rac1 and CDC42 have been widely shown to participate in cell proliferation, cell cycle and apoptosis, migration and invasion through a variety of signaling pathways 24-27. As main Rho GTPase family members 28, Rac1 and CDC42 function as molecular switches, cycling between two functional states, a GDP-bound, inactive state and a GTP-bound, active state. In the present study, pull-down and co-IP assays demonstrated that GINS4 directly binds to Rac1/CDC42 in vivo and in vitro .…”

Continuous ZnO nanoparticle exposure induces melanoma-like skin lesions in epidermal barrier dysfunction model mice through anti-apoptotic effects mediated by the oxidative stress–activated NF-κB pathway

“…Due to the increasing prevalence of diseases associated with epidermal barrier dysfunction, such as atopic dermatitis, eczema, and acne, whether the repetitive application of ZnO NPs to damaged skin is associated with an increased risk of penetration into the deep skin layers must be determined [1,12]. In our study, we used a mouse model of epidermal barrier dysfunction, in which skin damage was caused by the skin keratinocyte-specific deletion of Cdc42 [10].…”

“…The physical skin barrier is mainly localized in the stratum corneum, which plays a critical role in preventing damage due to environmental stress [9]. Zhang et al found that Cdc42 is essential for epidermal barrier formation, and Cdc42 deficiency might be associated with skin barrier damage or dysfunction [10].…”

Continuous ZnO nanoparticle exposure induces melanoma-like skin lesions in epidermal barrier dysfunction model mice through anti-apoptotic effects mediated by the oxidative stress–activated NF-κB pathway

“…Zhang et al found that Cdc42 played crucial roles in regulating the balance between keratinocyte proliferation and differentiation and in the integrity of cell–cell junctions in epidermal development. Cdc42 is essential for epidermal barrier formation, and Cdc42 deficiency might be associated with skin barrier damage or dysfunction [ 11 ].…”