Premature infants are at an increased risk for infections and dehydration because of incomplete development of the epidermis, which attains its essential function as a barrier only during the last stages of in utero development. When a premature birth is anticipated, antenatal corticosteroids are administered to accelerate lung epithelium differentiation. One pleiotropic, but beneficial, effect of antenatal corticosteroids is acceleration of skin barrier establishment by an unknown mechanism. In mice, the transcription factor Klf4 is both necessary and sufficient, within a developmental field of competence, to establish this skin barrier, as demonstrated by targeted ablation and transgenic expression of Klf4, respectively. Here, we report that Klf4 and corticosteroid treatment coordinately accelerate barrier acquisition in vivo. Transcriptional profiling reveals that the genes regulated by corticosteroids and Klf4 during the critical window of epidermal development significantly overlap. KLF4 activates the proximal promoters of a significant subset of these genes. Dissecting the intersection of the genetic and pharmacological pathways, regulated by KLF4 and corticosteroids, respectively, leads to a mechanistic understanding of the normal process of epidermal development in utero.development ͉ transcription factor ͉ skin ͉ glucocorticoid receptor

Small PRoline Rich (SPRR) proteins are primary constituents of the cornified cell envelope, necessary to create a permeability barrier across the body's surface. The family of murine Sprr genes has diversified, enabling the body to construct slightly different types of barriers as needed for backskin, mouth, tongue, etc. The Sprr genes have remained tandemly arrayed within 220 kb on mouse Chromosome (Chr) 3. On the basis of sequence similarity, we identified a novel member of the family, the murine ortholog of SPRR4. We present a sequence-verified physical map of the region and identify the complete coding sequence of the Sprr2 genes. Highly specific RNase protection assays based on the 3' untranslated sequences were used to query the expression of these genes in a model of barrier deficiency, mice with a targeted ablation of the transcription factor Kruppel-like factor 4 (Klf4-/-). Twelve of the 15 members of the Sprr family are upregulated in the Klf4-/- mice. The sequences upstream of the start of transcription of the Sprr2 genes contain common regulatory elements conserved with the human SPRR2 genes. The clustering of the genes and their misregulation suggest that these genes may be held together in a tandem array to allow coordinate regulation.

The results demonstrate that bipolar affective disorder occurs across all of the major European mtDNA haplogroups but do not reveal any point mutations that explain excess maternal transmission of the disorder.

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