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Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1.

ABSTRACT: The cornified layer is a compacted lattice of lipid-embedded corneocytes that provides an organism's barrier to the external environment. Cornification is the final differentiative step for epidermal keratinocytes and involves dramatic cell condensation before death. Using conditional gene deletion in mice, we identified the transcriptional repressor Blimp-1 (B lymphocyte-induced maturation protein-1) as an important regulator of keratinocyte transition from the granular to the cornified layer. More than 250 genes are misregulated in conditional knockout epidermis, including those encoding transcription factors, signal transduction components, proteinases, and enzymes involved in lipid metabolism. Steady-state mRNA and ChIP analyses of a subset of these genes provide evidence that nfat5, fos, prdm1, and dusp16 are novel direct targets of Blimp-1. Identifying nfat5 as a target of Blimp-1 repression indicates that cornification involves suppression of normal osmotic regulation in granular cells. Consistently, conditional knockout mice have delayed barrier formation as embryos, enlarged granular layer cells and corneocytes, and a morphologically abnormal cornified layer. These studies provide insight into cornification, identifying transcriptional regulatory circuitry and indicating the importance of blocking osmotic homeostasis.

SUBMITTER: Magnusdottir E

PROVIDER: S-EPMC1986600 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1.

Magnúsdóttir Erna E Kalachikov Sergey S Mizukoshi Koji K Savitsky David D Ishida-Yamamoto Akemi A Panteleyev Andrey A AA Calame Kathryn K

Proceedings of the National Academy of Sciences of the United States of America 20070910 38

The cornified layer is a compacted lattice of lipid-embedded corneocytes that provides an organism's barrier to the external environment. Cornification is the final differentiative step for epidermal keratinocytes and involves dramatic cell condensation before death. Using conditional gene deletion in mice, we identified the transcriptional repressor Blimp-1 (B lymphocyte-induced maturation protein-1) as an important regulator of keratinocyte transition from the granular to the cornified layer. ...[more]

PMID: 17846422

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Project description:BackgroundUpon antigen encounter, naïve B lymphocytes differentiate into antibody-secreting plasma cells. This humoral immune response is suppressed by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxin-like compounds, which belong to the family of aryl hydrocarbon receptor (AhR) agonists.ResultsTo achieve a better understanding of the immunotoxicity of AhR agonists and their associated health risks, we have used computer simulations to study the behavior of the gene regulatory network underlying B cell terminal differentiation. The core of this network consists of two coupled double-negative feedback loops involving transcriptional repressors Bcl-6, Blimp-1, and Pax5. Bifurcation analysis indicates that the feedback network can constitute a bistable system with two mutually exclusive transcriptional profiles corresponding to naïve B cells and plasma cells. Although individual B cells switch to the plasma cell state in an all-or-none fashion when stimulated by the polyclonal activator lipopolysaccharide (LPS), stochastic fluctuations in gene expression make the switching event probabilistic, leading to heterogeneous differentiation response among individual B cells. Moreover, stochastic gene expression renders the dose-response behavior of a population of B cells substantially graded, a result that is consistent with experimental observations. The steepness of the dose response curve for the number of plasma cells formed vs. LPS dose, as evaluated by the apparent Hill coefficient, is found to be inversely correlated to the noise level in Blimp-1 gene expression. Simulations illustrate how, through AhR-mediated repression of the AP-1 protein, TCDD reduces the probability of LPS-stimulated B cell differentiation. Interestingly, stochastic simulations predict that TCDD may destabilize the plasma cell state, possibly leading to a reversal to the B cell phenotype.ConclusionOur results suggest that stochasticity in gene expression, which renders a graded response at the cell population level, may have been exploited by the immune system to launch humoral immune response of a magnitude appropriately tuned to the antigen dose. In addition to suppressing the initiation of the humoral immune response, dioxin-like compounds may also disrupt the maintenance of the acquired immunity.

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Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1.

Publications

Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1.

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