Mazur, Pawel K., Grüner, 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 KrasG12D-induced skin carcinogenesis in vivo. PL o S One, Vol.5 (No.10). doi:10.1371/journal.pone.0013578

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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 KrasG12D mice with ablation of Notch1 and/or Notch2.

Methodology/Principal Findings
Surprisingly, mice with activated KrasG12D 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 β-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 > QP Physiology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions:	Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) > Biological Sciences ( -2010) Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH):	Notch proteins, GTPase-activating protein, Carcinogenesis, Skin -- Tumors
Journal or Publication Title:	PL o S One
Publisher:	Public Library of Science
ISSN:	1932-6203
Official Date:	22 October 2010
Dates:	Date Event 22 October 2010 Published
Volume:	Vol.5
Number:	No.10
DOI:	10.1371/journal.pone.0013578
Status:	Peer Reviewed
Access rights to Published version:	Open Access
Funder:	Deutsche Krebshilfe [German Cancer Aid], Lustgarten Foundation, Deutsche Forschungsgemeinschaft (DFG)
Grant number:	107195 (DK), RFP05-14 (LF), RFP06-12 (LF), SI 1549/1-1 (DFG)

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