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First published online 17 September 2009
doi: 10.1242/dev.037010

Development 136, 3423-3431 (2009)
Published by The Company of Biologists 2009
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Akt-dependent Pp2a activity is required for epidermal barrier formation during late embryonic development

Ryan F. L. O'Shaughnessy1,2,*, Jonathan C. Welti1, Katherine Sully1 and Carolyn Byrne1,3

1 Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Whitechapel, London E1 2AD, UK.
2 Dermatology and Immunobiology, Institute of Child Health, University College London, London WC1N 1EH, UK.
3 Cancer Research UK Skin Tumour Laboratory, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry.

* Author for correspondence (r.oshaughnessy{at}ich.ucl.ac.uk)

Accepted 12 August 2009

Acquisition of epidermal barrier function occurs late in mouse gestation. Several days before birth a wave of barrier acquisition sweeps across murine fetal skin, converging on dorsal and ventral midlines. We investigated the molecular pathways active during epidermal barrier formation. Akt signaling increased as the barrier wave crossed epidermis and Jun was transiently dephosphorylated. Inhibitor experiments on embryonic explants showed that the dephosphorylation of Jun was dependent on both Akt and protein phosphatase 2A (Pp2a). Inhibition of Pp2a and Akt signaling also caused defects in epidermal barrier formation. These data are compatible with a model for developmental barrier acquisition mediated by Pp2a regulation of Jun dephosphorylation, downstream of Akt signaling. Support for this model was provided by siRNA-mediated knockdown of Ppp2r2a (Pr55{alpha} or B55{alpha}), a regulatory subunit of Pp2a expressed in an Akt-dependent manner in epidermis during barrier formation. Ppp2r2a reduction caused significant increase in Jun phosphorylation and interfered with the acquisition of barrier function, with barrier acquisition being restored by inhibition of Jun phosphorylation. Our data provide strong evidence that Ppp2r2a is a regulatory subunit of Pp2a that targets this phosphatase to Jun, and that Pp2a action is necessary for barrier formation. We therefore describe a novel Akt-dependent Pp2a activity that acts at least partly through Jun to affect initial barrier formation during late embryonic epidermal development.

Key words: Epidermis, Barrier function, Akt, Jun, c-jun, Phosphatase, Pp2a, Ppp2r2a, Mouse


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