title: Pelota Regulates Epidermal Differentiation by Modulating BMP and PI3K/AKT Signaling Pathways.
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.
authors.affiliation: Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany; Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: Manar
authors.initials: M
authors.lastname: Elkenani
authors.affiliation: Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany.
authors.forename: Gunsmaa
authors.initials: G
authors.lastname: Nyamsuren
authors.affiliation: Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany.
authors.forename: Priyadharsini
authors.initials: P
authors.lastname: Raju
authors.affiliation: 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.
authors.forename: Kifayathullah
authors.initials: K
authors.lastname: Liakath-Ali
authors.affiliation: Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany.
authors.forename: Aicha
authors.initials: A
authors.lastname: Hamdaoui
authors.affiliation: Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kata
authors.affiliation: Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, D-37073 Göttingen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dressel
authors.affiliation: Department of Human Anatomy and Cell Science, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klonisch
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital Campus, London, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
authors.affiliation: Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Engel
authors.affiliation: Department of Human Anatomy and Cell Science, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Thliveris
authors.affiliation: 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.
authors.forename: D V
authors.initials: DV
authors.lastname: Krishna Pantakani
authors.affiliation: Institute of Human Genetics, University of Göttingen, D-37073 Göttingen, Germany. Electronic address: iadham@gwdg.de.
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Adham
mesh_terms: D000483:Alleles; D000818:Animals; D001835:Body Weight; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D004720:Endonucleases; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D000091344:Filaggrin Proteins; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D010539:Permeability; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D018797:Cell Cycle Proteins; D004720:Endonucleases; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C000717249:FLG protein, human; C000590334:Pelo protein, mouse