Mazur, Pawel K., Gruener, Barbara M., Nakhai, Hassan, Sipos, Bence, Zimber-Strobl, Ursula, Strobl, Lothar J., Radtke, Freddy, Schmid, Roland M. and Siveke, Jens T.. (2010) Identification of epidermal Pdx1 expression discloses different roles of Notch1 and Notch2 in Murine Kras(G12D)-induced skin carcinogenesis in vivo. PLoS One, Vol.5 (No.10). Article no. e13578. ISSN 1932-6203

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Abstract

Background: The Ras and Notch signaling pathways are frequently activated during development to control many diverse cellular processes and are often dysregulated during tumorigenesis. To study the role of Notch and oncogenic Kras signaling in a progenitor cell population, Pdx1-Cre mice were utilized to generate conditional oncogenic Kras(G12D) mice with ablation of Notch1 and/or Notch2. Methodology/Principal Findings: Surprisingly, mice with activated Kras(G12D) and Notch1 but not Notch2 ablation developed skin papillomas progressing to squamous cell carcinoma providing evidence for Pdx1 expression in the skin. Immunostaining and lineage tracing experiments indicate that PDX1 is present predominantly in the suprabasal layers of the epidermis and rarely in the basal layer. Further analysis of keratinocytes in vitro revealed differentiation-dependent expression of PDX1 in terminally differentiated keratinocytes. PDX1 expression was also increased during wound healing. Further analysis revealed that loss of Notch1 but not Notch2 is critical for skin tumor development. Reasons for this include distinct Notch expression with Notch1 in all layers and Notch2 in the suprabasal layer as well as distinctive p21 and beta-catenin signaling inhibition capabilities. Conclusions/Significance: Our results provide strong evidence for epidermal expression of Pdx1 as of yet not identified function. In addition, this finding may be relevant for research using Pdx1-Cre transgenic strains. Additionally, our study confirms distinctive expression and functions of Notch1 and Notch2 in the skin supporting the importance of careful dissection of the contribution of individual Notch receptors.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science
Divisions:	Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010)
Journal or Publication Title:	PLoS One
Publisher:	Public Library of Science
ISSN:	1932-6203
Date:	22 October 2010
Volume:	Vol.5
Number:	No.10
Number of Pages:	12
Page Range:	Article no. e13578
Identification Number:	10.1371/journal.pone.0013578
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	German Cancer Aid, The Lustgarten Foundation, German Research Foundation
Grant number:	107195, RFP05-14, 06-12, SI 1549/1-1
URI:	http://wrap.warwick.ac.uk/id/eprint/4956

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