DeltaNp63 knockdown mice: A mouse model for AEC syndrome.
Dominant mutations in TP63 cause ankyloblepharon ectodermal dysplasia and clefting (AEC), an ectodermal dysplasia characterized by skin fragility. Since DeltaNp63alpha is the predominantly expressed TP63 isoform in postnatal skin, we hypothesized that mutant DeltaNp63alpha proteins are primarily responsible for skin fragility in AEC patients. We found that mutant DeltaNp63alpha proteins expressed in AEC patients function as dominant-negative molecules, suggesting that the human AEC skin phenotype could be mimicked in mouse skin by downregulating DeltaNp63alpha. Indeed, downregulating DeltaNp63 expression in mouse epidermis caused severe skin erosions, which resembled lesions that develop in AEC patients. In both cases, lesions were characterized by suprabasal epidermal proliferation, delayed terminal differentiation, and basement membrane abnormalities. By failing to provide structural stability to the epidermis, these defects likely contribute to the observed skin fragility. The development of a mouse model for AEC will allow us to further unravel the genetic pathways that are normally regulated by DeltaNp63 and that may be perturbed in AEC patients. Ultimately, these studies will not only contribute to our understanding of the molecular mechanisms that cause skin fragility in AEC patients, but may also result in the identification of targets for novel therapeutic approaches aimed at treating skin erosions. (c) 2009 Wiley-Liss, Inc.
Koster
Maranke I
MI
Department of Dermatology and Charles C. Gates Regenerative Medicine and Stem Cell Biology Program, University of Colorado-Denver, Aurora, CO 80045, USA. Maranke.Koster@ucdenver.edu
Marinari
Barbara
B
Payne
Aimee S
AS
Kantaputra
Piranit N
PN
Costanzo
Antonio
A
Roop
Dennis R
DR
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation; D002971:Cleft Lip / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D002972:Cleft Palate / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D000078404:Epidermal Cells; D005143:Eyelids / Q000002:abnormalities*; D005528:Foot / Q000473:pathology; D006225:Hand / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D012867:Skin / Q000473:pathology*; D013577:Syndrome; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics
C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
Hum Mol Genet. 2002 Apr 1;11(7):799-804
11929852
Am J Hum Genet. 2001 Sep;69(3):481-92
11462173
Clin Genet. 2004 Jul;66(1):79-80
15200513
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3255-60
17360634
Cell. 2007 May 4;129(3):523-36
17482546
Arch Dermatol. 2005 Dec;141(12):1591-4
16365264
Am J Hum Genet. 2000 Jul;67(1):59-66
10839977
Br J Dermatol. 1976 Mar;94(3):277-89
946410
Clin Genet. 2000 Dec;58(6):415-30
11149610
Hum Mol Genet. 2008 Jul 1;17(13):1968-77
18364388
Mol Cell. 1998 Sep;2(3):305-16
9774969
J Invest Dermatol. 2008 Jul;128(7):1617-9
18548078
Genes Dev. 2006 Nov 15;20(22):3185-97
17114587
Cell Cycle. 2007 Feb 1;6(3):262-8
17224651
J Invest Dermatol. 2009 Jan;129(1):60-9
18633439
Cell. 1999 Oct 15;99(2):143-53
10535733
J Dent Res. 2003 Jun;82(6):433-7
12766194
Nat Cell Biol. 2006 Jun;8(6):551-61
16715076
Mol Cell Biol. 2002 Dec;22(24):8659-68
12446784
Eur J Med Genet. 2006 Nov-Dec;49(6):520-2
16824815
Annu Rev Cell Dev Biol. 2007;23:93-113
17489688
Genes Dev. 2006 Apr 15;20(8):1028-42
16618808
Arch Dermatol. 2005 Dec;141(12):1567-73
16365259
Nucleic Acids Res. 2006 Feb 09;34(3):928-38
16473849
J Cell Biol. 1989 Sep;109(3):1207-17
2475508
Hum Mol Genet. 2001 Feb 1;10(3):221-9
11159940
Br J Dermatol. 1994 Jan;130(1):97-101
8305327