Transgenic over-expression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells.
The miR-17-92 locus encodes a cluster of 7 microRNAs transcribed as a single primary transcript. It can accelerate c-Myc induced B cell lymphoma development and is highly expressed in many tumors, including lung tumors. However, the role of miR-17-92 in development has not been well studied. From analysis of microRNAs during lung development, expression of the miR-17-92 cluster is high at early stages, but declines as development proceeds. We used the mouse surfactant protein C (Sftpc) promoter to over-express the cluster in embryonic lung epithelium. Transgenic lungs have a very abnormal lethal phenotype. They contain numerous proliferative epithelial cells that retain high levels of Sox9, a marker of distal progenitors. The differentiation of proximal epithelial cells was also inhibited. Furthermore, a significant increase in the number of neuroendocrine cell clusters was observed in the lungs of dead transgenic pups. We identify a tumor suppressor, Rbl2 which belongs to the Rb family, as a new target for miR-17-5p. Together, these studies suggest that mir-17-92 normally promotes the high proliferation and undifferentiated phenotype of lung epithelial progenitor cells.
Lu
Yun
Y
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Thomson
J Michael
JM
Wong
Ho Yuen Frank
HY
Hammond
Scott M
SM
Hogan
Brigid L M
BL
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D037721:Pulmonary Surfactant-Associated Protein C; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse