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

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

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.

MeSH terms

  • Alleles
  • Animals
  • Body Weight
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation
  • Cell Proliferation
  • Endonucleases
  • Epidermis / metabolism*
  • Female
  • Gene Deletion
  • Gene Expression Regulation, Developmental*
  • Intermediate Filament Proteins / metabolism*
  • Keratinocytes / cytology
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / metabolism*
  • Microscopy, Electron, Transmission
  • Permeability
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction*

Substances

  • Bone Morphogenetic Proteins
  • Cell Cycle Proteins
  • Intermediate Filament Proteins
  • Microfilament Proteins
  • filaggrin
  • Proto-Oncogene Proteins c-akt
  • Endonucleases
  • Pelo protein, mouse