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Notch signaling as a key determinant of Epithelial-Mesenchymal interactions in the skin

English title Notch signaling as a key determinant of Epithelial-Mesenchymal interactions in the skin
Applicant Dotto Gian-Paolo
Number 122281
Funding scheme Project funding (Div. I-III)
Research institution Centre Integratif de Genomique Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Molecular Biology
Start/End 01.10.2008 - 30.09.2011
Approved amount 880'058.05
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All Disciplines (6)

Discipline
Molecular Biology
Dermatology
Experimental Cancer Research
Genetics
Embryology, Developmental Biology
Cellular Biology, Cytology

Keywords (16)

epithelial-mesenchymal interactions; skin; keratinocytes; dermal papilla cells; dermal fibroblasts; Notch signaling; organ morphogenesis; aging; cancer; Notch; Wnt5a; Noggin; FGF; hair follicle keratinocyte cell fate; epithelial mesenchymal interactions; squamous cell carcinoma (SCC) formation

Lay Summary (English)

Lead
Lay summary
Epithelial-mesenchymal interactions play a determining function in organ morphogenesis, tissue homeostasis and carcinogenesis. Notch signaling is an important form of cell-cell communication with a key role in control of cell fate commitment. The role of this pathway in the epithelial cell compartments of organs like the skin is by now well established. Our main working hypothesis is that Notch signaling plays an equally important role in the underlying mesenchyme. We have been pursuing the following topics: A) We have been assessing the function of Notch signaling in specialized mesenchymal cells embedded in hair follicles, dermal papilla cells. We have found that this pathway is essential for hair follicle development and differentiation. Genetic abrogation of Notch signaling leads to dermal papilla cells that are intrinsically defective in their hair follicle inductive properties. Mechanistically, this is due to defective production of a diffusible growth factor, Wnt5a that provides an instructive signal, under normal conditions, to hair follicle keratinocytes. B) Dermal fibroblasts have a different embryonic origin than dermal papilla cells, and play a more general role in control of skin homeostasis and carcinogenesis. Changes of stromal cells have also been implicated as a determinant of the exponential increase of epithelial tumors with older age. Thus, the second aim of our work is to test the hypothesis that Notch signaling plays also a key function in dermal fibroblasts, in control of proliferation of overlying keratinocytes and keratinocyte tumor formation. We are further testing the hypothesis that this function is mediated by transcriptional control of genes that impinge through paracrine mechanisms, on neighboring keratinocytes.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes.
Restivo Gaetana, Nguyen Bach-Cuc, Dziunycz Piotr, Ristorcelli Elodie, Ryan Russell J H, Ozuysal Ozden Yalçin, Di Piazza Matteo, Radtke Freddy, Dixon Michael J, Hofbauer Günther F L, Lefort Karine, Dotto G Paolo (2011), IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes., in The EMBO journal, 30(22), 4571-4585.
p63 and epithelial metaplasia: a gutsy choice.
Lefort Karine, Dotto G Paolo (2011), p63 and epithelial metaplasia: a gutsy choice., in Cell, 145(7), 1003-5.
Calcineurin signaling as a negative determinant of keratinocyte cancer stem cell potential and carcinogenesis.
Dotto G Paolo (2011), Calcineurin signaling as a negative determinant of keratinocyte cancer stem cell potential and carcinogenesis., in Cancer research, 71(6), 2029-33.
Differential control of Notch1 gene transcription by Klf4 and Sp3 transcription factors in normal versus cancer-derived keratinocytes.
Lambertini Chiara, Pantano Serafino, Dotto G Paolo (2010), Differential control of Notch1 gene transcription by Klf4 and Sp3 transcription factors in normal versus cancer-derived keratinocytes., in PloS one, 5(4).
Control of hair follicle cell fate by underlying mesenchyme through a CSL-Wnt5a-FoxN1 regulatory axis.
Hu Bing, Lefort Karine, Qiu Wenying, Nguyen Bach-Cuc, Rajaram Renuga Devi, Castillo Einar, He Fenglei, Chen Yiping, Angel Peter, Brisken Cathrin, Dotto G Paolo (2010), Control of hair follicle cell fate by underlying mesenchyme through a CSL-Wnt5a-FoxN1 regulatory axis., in Genes & development, 24(14), 1519-32.
Opposing roles for calcineurin and ATF3 in squamous skin cancer.
Wu Xunwei, Nguyen Bach-Cuc, Dziunycz Piotr, Chang Sungeun, Brooks Yang, Lefort Karine, Hofbauer Günther F L, Dotto G Paolo (2010), Opposing roles for calcineurin and ATF3 in squamous skin cancer., in Nature, 465(7296), 368-72.
A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans.
Mandinova Anna, Kolev Vihren, Neel Victor, Hu Bing, Stonely Wesley, Lieb Jocelyn, Wu Xunwei, Colli Claudia, Han Rong, Pazin Michael J, Pazin Mike, Ostano Paola, Dummer Reinhard, Brissette Janice L, Dotto G Paolo (2009), A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans., in The Journal of clinical investigation, 119(10), 3127-37.
Crosstalk of Notch with p53 and p63 in cancer growth control.
Dotto G Paolo (2009), Crosstalk of Notch with p53 and p63 in cancer growth control., in Nature reviews. Cancer, 9(8), 587-95.
Impact of normalization on miRNA microarray expression profiling.
Pradervand Sylvain, Weber Johann, Thomas Jérôme, Bueno Manuel, Wirapati Pratyaksha, Lefort Karine, Dotto G Paolo, Harshman Keith (2009), Impact of normalization on miRNA microarray expression profiling., in RNA (New York, N.Y.), 15(3), 493-501.
Notch tumor suppressor function.
Dotto G P (2008), Notch tumor suppressor function., in Oncogene, 27(38), 5115-23.
EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer.
Kolev Vihren, Mandinova Anna, Guinea-Viniegra Juan, Hu Bing, Lefort Karine, Lambertini Chiara, Neel Victor, Dummer Reinhard, Wagner Erwin F, Dotto G Paolo (2008), EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer., in Nature cell biology, 10(8), 902-11.
The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response.
Mandinova Anna, Lefort Karine, Tommasi di Vignano Alice, Stonely Wesley, Ostano Paola, Chiorino Giovanna, Iwaki Haruhi, Nakanishi Jotaro, Dotto G Paolo (2008), The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response., in The EMBO journal, 27(8), 1243-54.

Associated projects

Number Title Start Funding scheme
102212 La calcineurine dans le contrôle de la croissance-différenciation 01.10.2003 Project funding (Div. I-III)
138653 Control of Notch1 Gene Transcription in skin homeostasis and carcinogenesis 01.10.2011 Project funding (Div. I-III)

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