Abstract
BackgroundThe Wnt signaling system plays key roles in development, regulation of stem cell self-renewal and differentiation, cell polarity, morphogenesis and cancer. Given the multifaceted roles of Wnt signaling in these processes, its transcriptional effects on the stromal cells that make up the scaffold and infrastructure of epithelial tissues are of great interest.Methods and ResultsTo begin to investigate these effects, we used DNA microarrays to identify transcriptional targets of the Wnt pathway in human lung fibroblasts. Cells were treated with active Wnt3a protein in culture, and RNA was harvested at 4 hours and 24 hours. Nuclear accumulation of ß-Catenin, as shown by immunofluorescence, and induction of AXIN2 demonstrate that fibroblasts are programmed to respond to extracellular Wnt signals. In addition to several known Wnt targets, we found many new Wnt induced genes, including many transcripts encoding regulatory proteins. Transcription factors with important developmental roles, including HOX genes, dominated the early transcriptional response. Furthermore, we found differential expression of several genes that play direct roles in the Wnt signaling pathway, as well as genes involved in other cell signaling pathways including fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signaling. The gene most highly induced by Wnt3a was GREMLIN2, which encodes a secreted BMP antagonist.ConclusionsElevated expression of GREMLIN2 suggests a new role for Wnt signals in the maintenance of stem cell niches, whereby Wnt signals induce nearby fibroblasts to produce a BMP antagonist, inhibiting differentiation and promoting expansion of stem cells in their microenvironment. We suggest that Wnt-induced changes in the gene expression program of local stromal cells may play an important role in the establishment of specialized niches hospitable to the self-renewal of normal or malignant epithelial stem cells in vivo.
Highlights
Wnt genes encode conserved, secreted signaling molecules that play important roles in numerous aspects of metazoan development, including stem cell regulation, fate determination, body axis specification, cell polarity, proliferation and differentiation [1]
Wnt3a treatment of human lung fibroblasts (HLF) in culture resulted in induction or repression of several genes that have been identified as Wnt targets in other cell types (e.g. AXIN2, DKK1, TWIST1, MMP11), as well as many genes not previously identified as targets of Wnt signal transduction (Figure 2A)
We identified 215 genes that were consistently induced or repressed in response to Wnt3a, after either 4 or 24 hours, or both, using significance analysis of microarrays (SAM), with a false-discovery rate (FDR) of less than 1% (Supplemental Dataset S1, Supplemental Figure S1)
Summary
Wnt genes encode conserved, secreted signaling molecules that play important roles in numerous aspects of metazoan development, including stem cell regulation, fate determination, body axis specification, cell polarity, proliferation and differentiation [1]. We found differential expression of several genes that play direct roles in the Wnt signaling pathway, as well as genes involved in other cell signaling pathways including fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signaling. Elevated expression of GREMLIN2 suggests a new role for Wnt signals in the maintenance of stem cell niches, whereby Wnt signals induce nearby fibroblasts to produce a BMP antagonist, inhibiting differentiation and promoting expansion of stem cells in their microenvironment. We suggest that Wnt-induced changes in the gene expression program of local stromal cells may play an important role in the establishment of specialized niches hospitable to the self-renewal of normal or malignant epithelial stem cells in vivo
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