Abstract
The epidermal permeability barrier (EPB) prevents organisms from dehydration and infection. The transcriptional regulation of EPB development is poorly understood. We demonstrate here that transcription factor COUP-TF-interacting protein 1 (CTIP1/BCL11A; hereafter CTIP1) is highly expressed in the developing murine epidermis. Germline deletion of Ctip1 (Ctip1−/−) results in EPB defects accompanied by compromised epidermal differentiation, drastic reduction in profilaggrin processing, reduced lamellar bodies in granular layers and significantly altered lipid composition. Transcriptional profiling of Ctip1−/− embryonic skin identified altered expression of genes encoding lipid-metabolism enzymes, skin barrier-associated transcription factors and junctional proteins. CTIP1 was observed to interact with genomic elements within the regulatory region of the gene encoding the differentiation-associated gene, Fos-related antigen2 (Fosl2) and lipid-metabolism-related gene, Fatty acid elongase 4 (Elvol4), and the expression of both was altered in Ctip1−/− mice. CTIP1 appears to play a role in EPB establishment of via direct or indirect regulation of a subset of genes encoding proteins involved in epidermal differentiation and lipid metabolism. These results identify potential, CTIP1-regulated avenues for treatment of skin disorders involving EBP defects.
Highlights
The most important epidermal sphingolipids and most abundant lipid types (50% by weight)
CTIP1 co-localized with keratin 14 (K14) in the ectoderm E10.5 and E12.5 (Fig. 1a,b)
The present study reveals a previously unidentified role for the transcription factor CTIP1 in establishment and formation of epidermal permeability barrier during development
Summary
The most important epidermal sphingolipids and most abundant lipid types (50% by weight). A variety of transcription factors (TFs) and signaling pathways are crucial for establishing the functional epidermal permeability barrier (EPB). We have shown that CTIP2 is highly expressed in skin and plays a significant role in barrier establishment, lipid metabolism and epidermal homeostasis, as well as in hair follicle morphogenesis and hair cycling[14,34,35]. The expression pattern of CTIP1 in skin and its functions in EPB formation, epidermal proliferation and differentiation during development are unknown. Altered expression of genes encoding lipid-metabolism enzymes, skin barrier-associated TFs, and junctional proteins (JPs) was observed in Ctip1−/− embryonic skin. This study describes a new in vivo role of CTIP1 in establishing the epidermal permeability barrier during murine skin morphogenesis
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