论文信息 - p63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate

p63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate

Cleft palate is a common congenital disorder that affects up to 1 in 2500 live births and results in considerable morbidity to affected individuals and their families. The aetiology of cleft palate is complex with both genetic and environmental factors implicated. Mutations in the transcription factor p63 are one of the major individual causes of cleft palate; however, the gene regulatory networks in which p63 functions remain only partially characterized. Our findings demonstrate that p63 functions as an essential regulatory molecule in the spatio-temporal control of palatal epithelial cell fate to ensure appropriate fusion of the palatal shelves. Initially, p63 induces periderm formation and controls its subsequent maintenance to prevent premature adhesion between adhesion-competent, intra-oral epithelia. Subsequently, TGFβ3-induced down-regulation of p63 in the medial edge epithelia of the palatal shelves is a pre-requisite for palatal fusion by facilitating periderm migration from, and reducing the proliferative potential of, the midline epithelial seam thereby preventing cleft palate.

[1] J. Murray,et al. Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate , 2015, Human molecular genetics.

[2] S. Sinha,et al. TGFβ3 Regulates Periderm Removal Through ΔNp63 in the Developing Palate , 2015, Journal of cellular physiology.

[3] F. Brancati,et al. p63-dependent and independent mechanisms of nectin-1 and nectin-4 regulation in the epidermis , 2015, Experimental dermatology.

[4] M. Pisano,et al. Deciphering TGF‐β3 function in medial edge epithelium specification and fusion during mouse secondary palate development , 2014, Developmental dynamics : an official publication of the American Association of Anatomists.

[5] R. Salonen,et al. Periderm prevents pathological epithelial adhesions during embryogenesis. , 2014, The Journal of clinical investigation.

[6] I. Amelio,et al. p63 transcriptionally regulates the expression of matrix metallopeptidase 13 , 2014, Oncotarget.

[7] J. Kere,et al. Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. , 2014, American journal of human genetics.

[8] R. Pelikan,et al. Smad4-Irf6 genetic interaction and TGFβ-mediated IRF6 signaling cascade are crucial for palatal fusion in mice , 2013, Development.

[9] R. Redett,et al. Cleft Lip and Palate , 2013, Eplasty.

[10] M. Leid,et al. Ctip2 is a dynamic regulator of epidermal proliferation and differentiation by integrating EGFR and Notch signaling , 2012, Journal of Cell Science.

[11] C. Missero,et al. p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome , 2012, Human molecular genetics.

[12] Dan E. Webster,et al. Genomic profiling of a human organotypic model of AEC syndrome reveals ZNF750 as an essential downstream target of mutant TP63. , 2012, American journal of human genetics.

[13] T. Komori,et al. Periderm cells covering palatal shelves have tight junctions and their desquamation reduces the polarity of palatal shelf epithelial cells in palatogenesis , 2012, Genes to cells : devoted to molecular & cellular mechanisms.

[14] A. Ashworth,et al. Genome-wide analysis of p63 binding sites identifies AP-2 factors as co-regulators of epidermal differentiation , 2012, Nucleic acids research.

[15] Z. Siprashvili,et al. ZNF750 is a p63 target gene that induces KLF4 to drive terminal epidermal differentiation. , 2012, Developmental cell.

[16] B. Spencer‐Dene,et al. Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome , 2012, EMBO molecular medicine.

[17] R. Jiang,et al. Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development , 2012, Development.

[18] T. Beaty,et al. Cleft lip and palate: understanding genetic and environmental influences , 2011, Nature Reviews Genetics.

[19] S. Mundlos,et al. Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome. , 2010, American journal of human genetics.

[20] Bas E. Dutilh,et al. Genome-Wide Profiling of p63 DNA–Binding Sites Identifies an Element that Regulates Gene Expression during Limb Development in the 7q21 SHFM1 Locus , 2010, PLoS genetics.

[21] G. Dotto,et al. Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice. , 2010, The Journal of clinical investigation.

[22] Cory Y. McLean,et al. GREAT improves functional interpretation of cis-regulatory regions , 2010, Nature Biotechnology.

[23] Todd P. Michael,et al. Filtering error from SOLiD Output , 2010, Bioinform..

[24] S. Sinha,et al. An Active Role of the ΔN Isoform of p63 in Regulating Basal Keratin Genes K5 and K14 and Directing Epidermal Cell Fate , 2009, PloS one.

[25] M. Dixon,et al. Integration of IRF6 and Jagged2 signalling is essential for controlling palatal adhesion and fusion competence , 2009, Human molecular genetics.

[26] Lior Pachter,et al. Sequence Analysis , 2020, Definitions.

[27] Cole Trapnell,et al. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[28] Clifford A. Meyer,et al. Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[29] M. Dixon,et al. Facial clefting in Tp63 deficient mice results from altered Bmp4, Fgf8 and Shh signaling. , 2008, Developmental biology.

[30] D. di Bernardo,et al. Direct targets of the TRP63 transcription factor revealed by a combination of gene expression profiling and reverse engineering. , 2008, Genome research.

[31] Geping Zhao,et al. TFAP2A mutations result in branchio-oculo-facial syndrome. , 2008, American journal of human genetics.

[32] Michael J Dixon,et al. Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch , 2006, Nature Genetics.

[33] E. Cho,et al. Jag2‐Notch1 signaling regulates oral epithelial differentiation and palate development , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[34] Jason S. Carroll,et al. p63 regulates an adhesion programme and cell survival in epithelial cells , 2006, Nature Cell Biology.

[35] A. Mills,et al. p63 regulates multiple signalling pathways required for ectodermal organogenesis and differentiation , 2006, Development.

[36] R. Mantovani,et al. Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63 , 2006, Nucleic acids research.

[37] A. McMahon,et al. Fate-mapping of the epithelial seam during palatal fusion rules out epithelial-mesenchymal transformation. , 2005, Developmental biology.

[38] K. McGowan,et al. Exploiting the Keratin 17 Gene Promoter To Visualize Live Cells in Epithelial Appendages of Mice , 2005, Molecular and Cellular Biology.

[39] Rebecca A. Ihrie,et al. Perp Is a p63-Regulated Gene Essential for Epithelial Integrity , 2005, Cell.

[40] L. Covarrubias,et al. Death is the major fate of medial edge epithelial cells and the cause of basal lamina degradation during palatogenesis , 2004, Development.

[41] C. Shuler,et al. Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects , 2003, Development.

[42] John D. Storey,et al. Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43] C. Shuler,et al. TGF‐β3–dependent SMAD2 phosphorylation and inhibition of MEE proliferation during palatal fusion , 2003, Developmental Dynamics.

[44] R. Mantovani,et al. Complex Transcriptional Effects of p63 Isoforms: Identification of Novel Activation and Repression Domains† , 2002, Molecular and Cellular Biology.

[45] Jeffrey C. Murray,et al. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes , 2002, Nature Genetics.

[46] Thomas D. Schmittgen,et al. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[47] A. Glick,et al. Conditional gene expression in the epidermis of transgenic mice using the tetracycline-regulated transactivators tTA and rTA linked to the keratin 5 promoter. , 2000, The Journal of investigative dermatology.

[48] R. Spritz,et al. Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia , 2000, Nature Genetics.

[49] E. Fuchs,et al. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[50] K. McGowan,et al. Onset of Keratin 17 Expression Coincides with the Definition of Major Epithelial Lineages during Skin Development , 1998, The Journal of cell biology.

[51] Francesco Cecconi,et al. Apaf1 (CED-4 Homolog) Regulates Programmed Cell Death in Mammalian Development , 1998, Cell.

[52] A. Yang,et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. , 1998, Molecular cell.

[53] G. Weinmaster,et al. Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. , 1998, Genes & development.

[54] V. Kaartinen,et al. Abnormal lung development and cleft palate in mice lacking TGF–β3 indicates defects of epithelial–mesenchymal interaction , 1995, Nature Genetics.