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J Invest Dermatol. 2016 Aug;136(8):1664-1671. doi: 10.1016/j.jid.2016.04.020. Epub 2016 May 7.

Pelota Regulates Epidermal Differentiation by Modulating BMP and PI3K/AKT Signaling Pathways.

Author information

1
Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany; Faculty of Medicine, Mansoura University, Mansoura, Egypt.
2
Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany.
3
Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital Campus, London, UK; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Old Addenbrooke's Site, Cambridge, UK.
4
Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, D-37073 Göttingen, Germany.
5
Department of Human Anatomy and Cell Science, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
6
Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital Campus, London, UK.
7
Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany; Institute of Clinical Chemistry/UMG-Laboratories, University Medical Center Göttingen, D-37075, Göttingen, Germany.
8
Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany. Electronic address: iadham@gwdg.de.

Abstract

The depletion of evolutionarily conserved pelota protein causes impaired differentiation of embryonic and spermatogonial stem cells. In this study, we show that temporal deletion of pelota protein before epidermal barrier acquisition leads to neonatal lethality due to perturbations in permeability barrier formation. Further analysis indicated that this phenotype is a result of failed processing of profilaggrin into filaggrin monomers, which promotes the formation of a protective epidermal layer. Molecular analyses showed that pelota protein negatively regulates the activities of bone morphogenetic protein and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways in the epidermis. To address whether elevated activities of bone morphogenetic protein and PI3K/AKT signaling pathways were the cause for the perturbed epidermal barrier in Pelo-deficient mice, we made use of organotypic cultures of skin explants from control and mutant embryos at embryonic day 15.5. Inhibition of PI3K/AKT signaling did not significantly affect the bone morphogenetic protein activity. However, inhibition of bone morphogenetic protein signaling caused a significant attenuation of PI3K/AKT activity in mutant skin and, more interestingly, the restoration of profilaggrin processing and normal epidermal barrier function. Therefore, increased activity of the PI3K/AKT signaling pathway in Pelo-deficient skin might conflict with the dephosphorylation of profilaggrin and thereby affect its proper processing into filaggrin monomers and ultimately the epidermal differentiation.

PMID:
27164299
DOI:
10.1016/j.jid.2016.04.020
[Indexed for MEDLINE]
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