Identification of epidermal Pdx1 expression discloses different roles of Notch1 and Notch2 in murine Kras(G12D)-induced skin carcinogenesis in vivo.
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.


RESULTS
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 β-catenin signaling inhibition capabilities.


CONCLUSIONS
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.
2nd Department of Internal Medicine, Klinikum Rechts der Isar University Hospital, Technical University of Munich, Munich, Germany.
Pawel K
PK
Mazur
Barbara M
BM
Grüner
Hassan
H
Nakhai
Bence
B
Sipos
Ursula
U
Zimber-Strobl
Lothar J
LJ
Strobl
Freddy
F
Radtke
Roland M
RM
Schmid
Jens T
JT
Siveke
D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D017931:DNA Primers; D004817:Epidermis / Q000378:metabolism*; D011905:Genes, ras; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010212:Papilloma / Q000235:genetics / Q000473:pathology; D051881:Receptor, Notch1 / Q000502:physiology*; D051883:Receptor, Notch2 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics*; D051176:beta Catenin / Q000037:antagonists & inhibitors
D017931:DNA Primers; D018398:Homeodomain Proteins; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D015534:Trans-Activators; D051176:beta Catenin; C084010:pancreatic and duodenal homeobox 1 protein