DNp63 is an ectodermal gatekeeper of epidermal morphogenesis

R Shalom-Feuerstein, AM Lena, H Zhou, S De La Forest Divonne, H Van Bokhoven, E Candi, G Melino and D Aberdam


Cell Death and Differentiation (2011) 18, 887–896


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p63, a member of p53 family, has a significant role in the development and maintenance of stratified epithelia. However, a persistent dispute remained over the last decade concerning the interpretation of the severe failure of p63-null embryos to develop stratified epithelia. In this study, by investigating both p63-deficient strains, we demonstrated that p63-deficient epithelia failed to develop beyond ectodermal stage as they remained a monolayer of non-proliferating cells expressing K8/K18. Importantly, in the absence of p63, corneal-epithelial commitment (which occurs at embryonic day 12.5 of mouse embryogenesis) was hampered 3 weeks before corneal stem cell renewal (that begins at P14). Taken together, these data illustrate the significant role of p63 in epithelial embryogenesis, before and independently of other functions of p63 in adult stem cells regulation. Transcriptome analysis of laser captured-embryonic tissues confirmed the latter hypothesis, demonstrating that a battery of epidermal genes that were activated in wild-type epidermis remained silent in p63-null tissues. Furthermore, we defined a subset of novel bona fide p63-induced genes orchestrating first epidermal stratification and a subset of p63-repressed mesodermal-specific genes. These data highlight the earliest recognized action of DNp63 in the induction epidermal morphogenesis at E11.5. In the absence of p63, a mesodermal program is activated while epidermal morphogenesis does not initiate.


1. Blanpain C, Fuchs E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol 2009; 10: 207–217.

2. Candi E, Cipollone R, Rivetti di Val Cervo P, Gonfloni S, Melino G, Knight R. p63 in epithelial development. Cell Mol Life Sci 2008; 65: 3126–3133.

3. Crum CP, McKeon FD. p63 in epithelial survival, germ cell surveillance, and neoplasia. Annu Rev Pathol 2010; 5: 349–371.

4. Fuchs E. Scratching the surface of skin development. Nature 2007; 445: 834–842.

5. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999; 398: 708–713.

6. Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999; 398: 714–718.

7. Senoo M, Pinto F, Crum CP, McKeon F. p63 is essential for the proliferative potential of stem cells in stratified epithelia. Cell 2007; 129: 523–536.

8. Koster MI, Kim S, Mills AA, DeMayo FJ, Roop DR. p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev 2004; 18: 126–131.

9. Aberdam D, Gambaro K, Rostagno P, Aberdam E, de la Forest Divonne S, Rouleau M. Key role of p63 in BMP-4-induced epidermal commitment of embryonic stem cells. Cell Cycle 2007; 6: 291–294.

10. Medawar A, Virolle T, Rostagno P, de la Forest-Divonne S, Gambaro K, Rouleau M et al. DeltaNp63 is essential for epidermal commitment of embryonic stem cells. PLoS One 2008; 3: e3441.

11. Koster MI, Dai D, Roop DR. Conflicting roles for p63 in skin development and carcinogenesis. Cell Cycle 2007; 6: 269–273.

12. Findlater GS, McDougall RD, Kaufman MH. Eyelid development, fusion and subsequent reopening in the mouse. J Anat 1993; 183(Pt 1): 121–129.

13. Candi E, Rufini A, Terrinoni A, Giamboi-Miraglia A, Lena AM, Mantovani R et al. DeltaNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2. Proc Natl Acad Sci USA 2007; 104: 11999–12004.

14. Huang J, Dattilo LK, Rajagopal R, Liu Y, Kaartinen V, Mishina Y et al. FGF-regulated BMP signaling is required for eyelid closure and to specify conjunctival epithelial cell fate. Development 2009; 136: 1741–1750.

15. Carroll DK, Carroll JS, Leong CO, Cheng F, Brown M, Mills AA et al. p63 regulates an adhesion programme and cell survival in epithelial cells. Nat Cell Biol 2006; 8: 551–561.

16. Borrelli S, Candi E, Alotto D, Castagnoli C, Melino G, Vigano MA et al. p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis. Cell Death Differ 2009; 16: 253–263.

17. Truong AB, Kretz M, Ridky TW, Kimmel R, Khavari PA. p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev 2006; 20: 3185–3197.

18. Wolff S, Talos F, Palacios G, Beyer U, Dobbelstein M, Moll UM. The alpha/beta carboxyterminal domains of p63 are required for skin and limb development. New insights from the Brdm2 mouse which is not a complete p63 knockout but expresses p63 gamma-like proteins. Cell Death Differ 2009; 16: 1108–1117.

19. Dennis Jr G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 2003; 4: P3.

20. De Rosa L, Antonini D, Ferone G, Russo MT, Yu PB, Han R et al. p63 suppresses non-epidermal lineage markers in a bone morphogenetic protein-dependent manner via repression of Smad7. J Biol Chem 2009; 284: 30574–30582.

21. Miyake T, Alli NS, McDermott JC. Nuclear function of Smad7 promotes myogenesis. Mol Cell Biol 2010; 30: 722–735.

22. Barton CE, Tahinci E, Barbieri CE, Johnson KN, Hanson AJ, Jernigan KK et al. DeltaNp63 antagonizes p53 to regulate mesoderm induction in Xenopus laevis. Dev Biol 2009; 329: 130–139.

23. Barbieri CE, Tang LJ, Brown KA, Pietenpol JA. Loss of p63 leads to increased cell migration and up-regulation of genes involved in invasion and metastasis. Cancer Res 2006; 66: 7589–7597.

24. Rostagno P, Wolchinsky Z, Vigano AM, Shivtiel S, Zhou H, Van Bokhoven H et al. Embryonic stem cells as an ectodermal cellular model of human p63-related dysplasia syndromes. Biochem Biophys Res Commun 2010; 395: 131–135.

25. Blankenberg D, Taylor J, Schenck I, He J, Zhang Y, Ghent M et al. A framework for collaborative analysis of ENCODE data: making large-scale analyses biologist-friendly. Genome Res 2007; 17: 960–964.

26. Taylor J, Schenck I, Blankenberg D, Nekrutenko A. Using galaxy to perform large-scale interactive data analyses. Curr Protoc Bioinformatics 2007; Chapter 10 Unit 10 5.

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