The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
California Academy of Sciences, San Francisco, California, USA.
J Invest Dermatol. 2024 Feb;144(2):296-306.e3. doi: 10.1016/j.jid.2023.08.009. Epub 2023 Sep 3.
The epidermis is a constantly renewing stratified epithelial tissue that provides essential protective barrier functions. The major barrier is located at the outermost layers of the epidermis, formed by terminally differentiated keratinocytes reinforced by proteins of their cornified envelope and sequestered intercellular lipids. Disruptions to epidermal differentiation characterize various skin disorders. ZNF750 is an epithelial transcription factor essential for in vitro keratinocyte differentiation, whose truncating mutation in humans causes autosomal dominant psoriasis-like skin disease. In this study, we utilized an epidermal-specific Znf750 conditional knockout mouse model to uncover the role ZNF750 plays in epidermal development. We show that deletion of Znf750 in the developing skin does not block epidermal differentiation completely, suggesting in vivo compensatory feedback mechanisms, although it does result in impaired barrier function and perinatal lethality. Molecular dissection revealed ultrastructural defects in the differentiated layers of the epidermis, accompanied by alterations in the expression of ZNF750-dependent genes encoding key cornified envelope precursor proteins and lipid-processing enzymes, including gene subsets known to be mutated in human skin diseases involving impaired barrier function. Together, our findings provide molecular insights into the pathogenesis of human skin disease by linking ZNF750 to a subset of epidermal differentiation genes involved in barrier formation pathways.
表皮是一种不断更新的分层上皮组织，提供重要的保护屏障功能。主要屏障位于表皮的最外层，由终末分化的角质形成细胞形成，这些细胞由其角化包膜中的蛋白质和隔离的细胞间脂质加固。表皮分化的中断是各种皮肤疾病的特征。ZNF750 是一种上皮转录因子，对体外角质形成细胞分化至关重要，人类中该基因的截断突变会导致常染色体显性遗传的银屑病样皮肤疾病。在这项研究中，我们利用表皮特异性 Znf750 条件性敲除小鼠模型来揭示 ZNF750 在表皮发育中的作用。我们发现，在发育中的皮肤中删除 Znf750 并没有完全阻止表皮分化，这表明存在体内补偿反馈机制，尽管这确实导致了屏障功能受损和围产期致死。分子剖析显示，表皮分化层存在超微结构缺陷，同时伴有 ZNF750 依赖性基因表达的改变，这些基因编码关键的角化包膜前体蛋白和脂质处理酶，其中包括已知在涉及屏障功能受损的人类皮肤疾病中发生突变的基因亚组。总之，我们的研究结果通过将 ZNF750 与参与屏障形成途径的一组表皮分化基因联系起来，为人类皮肤疾病的发病机制提供了分子见解。
