B-lymphocyte induced maturation protein-1 (Blimp-1) is a transcriptional repressor best characterized for its ability to drive the terminal differentiation of B-lymphocytes to become antibody secreting plasma cells. However, Blimp-1 expression is not restricted to the B-lymphocyte lineage. Recently it was shown to be expressed in various different epithelia, including the keratinocytes of the skin ectoderm. In this work I have focused on the role of Blimp-1 in epidermal differentiation. I used mice harboring surface ectoderm specific deletion of prdm1, the gene encoding Blimp-1, to begin characterizing the role of Blimp-1 in skin. The resulting conditional knockout mice (CKO) had hyperkeratinized epidermis, transient hyperproliferation of neonatal epidermis, enlarged sebaceous glands and a mild defect in hair cycle regulation. Furthermore, the CKO animals showed signs of severe itchiness, as they scratched incessantly resulting in ulceration and scarring.

To avoid problems resulting from the scratching in adult animals, I focused on embryonic and neonatal epidermis, and showed that upon removal of Blimp-1, epidermal permeability barrier formation is delayed. Transmission electron microscopy, performed by a collaborator, and immunofluorescence labeling with antibodies to epidermal differentiation markers revealed that the transition of cells from granular to the most superficial cornified layer is delayed in neonatal epidermis. In addition, the granular and cornified layer cells were increased in size.

Transcriptional profiling revealed over 50 genes that were misregulated in the prdm1 CKO animals, including genes encoding transcription factors, signal transduction components, proteinases and lipid metabolism enzymes. I further identified four of those genes, fos, nfat5, dusp16 and prdm1 as direct targets of Blimp-1 repression, using chromatin immunoprecipitation. The discovery of a role for Blimp-1 in the repression of nfat5, a known regulator of the hyperosmotic shock responses, in the epidermis implies that during cornification the transcriptional control of cellular water content, employed in most other cells, needs to be abrogated. In addition, the identification of prdm1 as a direct target of Blimp-1 binding shows for the first time that Blimp-1 is involved in regulating its own expression levels.