Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm.
BACKGROUND
Studies in many model systems have shown that canonical signaling through the pathway downstream of ligands of the Wnt family can regulate multiple steps in organogenesis, including cell proliferation, differentiation, and lineage specification. In addition, misexpression of the Wnt-family member Wingless in Drosophila imaginal disc cells can lead to transdetermination of progenitors from one lineage to another. Conditional deletion of the beta-catenin component of the Wnt signaling pathway has indicated a role for Wnt signaling in mouse lung endoderm development. The full range of effects of this pathway, which includes the transcription factor Lef1, has not been explored, however.


RESULTS
To explore this issue, we expressed a constitutively active beta-catenin-Lef1 fusion protein in transgenic embryos using a lung-endoderm-specific promoter from the surfactant protein C gene. Transgenic lungs appeared grossly normal, but internally they contained highly proliferative, cuboidal epithelium lacking fully differentiated lung cell types. Unexpectedly, microarray analysis and in situ hybridization revealed a mosaic of cells expressing marker genes characteristic of intestinal Paneth and goblet cells and other non-lung secretory cell types. In addition, there was strong ectopic expression of genes such as Cdx1 and Atoh1 that normally regulate gut development and early allocation of cells to intestinal secretory lineages.


CONCLUSIONS
Our results show that hyperactive Wnt signaling in lung progenitors expressing a lung-specific gene can induce a dramatic switch in lineage commitment and the generation of intestinal cell types. We discuss the relevance of our findings to the poorly understood pathological condition of intestinal metaplasia in humans.
Okubo
Tadashi
T
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. t.okubo@cellbio.duke.edu
Hogan
Brigid L M
BL
D000818:Animals; D019070:Cell Lineage / Q000235:genetics; D004707:Endoderm / Q000737:chemistry / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D004848:Epithelium / Q000737:chemistry / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000737:chemistry / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D005796:Genes / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000737:chemistry; D008168:Lung / Q000196:embryology* / Q000254:growth & development* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D046228:Microarray Analysis / Q000379:methods; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D019076:Transgenes / Q000235:genetics; D051153:Wnt Proteins
D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins