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Wnt signalling
- The molecular basis of transdifferentiation

The Wnts are soluble secreted glycoproteins that interact with cell surface receptors belonging to the frizzled family. Wnt receptor activation leads to the inhibition of the threonine/serine kinase glycogen synthase kinase-3β (GSK-3β) and the stabilisation of β-catenin, which in turn can bind to transcription factors of the TCF/LEF-1 family and translocate to the nucleus to modulate expression of target genes [61]. Interestingly, several components of the Wnt signalling pathway are dynamically expressed during lung development. During epithelial branching, Wnt2 is expressed in the mesoderm adjacent to the tips of the branching endoderm which express Wnt7b [62], while the transcription factors TCF/LEF-1 are expressed in both mesoderm and endoderm [63]. In order to further study the role of Wnt signalling in the lung, Okubo and Hogan developed a transgenic mouse model in which an activated β-catenin-LEF-1 fusion protein was constitutively expressed under the control of the human surfactant protein C gene promoter [64]. Despite looking grossly normal, the transgenic lungs exhibited a drastically reduced number of Clara cells, a lack of fully differentiated alveolar type 1 and 2 cells and abnormally high proliferation of the bronchial epithelium. Subsequent microarray analysis and in situ hybridisation revealed the expression of multiple genes (trefoil factor 3, defensin related cryptidins 5, 6 and 15), characteristic of intestinal cell types such as Paneth and goblet cells, within the pulmonary epithelium of transgenic lungs. Furthermore, transgenic lungs showed induction or upregulation in the expression of a number of transcription factors that are components or targets of the Notch signalling pathway. These factors include Atoh 1 (Math1), not normally expressed in the lung but active in progenitor cells of the intestine [65], Gfi1, found in the neuroendocrine precursors of the gut and the lung [66] and increased levels of the Delta/Notch components Mash1, NeuroD4 and Delta-like 3. It appears that overactivation of Wnt signalling in the pulmonary epithelium leads to the respecification of pulmonary precursors towards cells of an intestinal cell fate, a process known as transdetermination. Wnt signalling is required in the developing intestine for the proliferation, maintenance and cell fate determination of epithelial stem cells in combination with the activity of the Notch signalling pathway [44, 65, 67]. Given that overactivation of the Wnt signalling pathway in the pulmonary epithelium leads to upregulation of several Notch signalling components, it is possible that the observed switch from a pulmonary to intestinal cell fate is dependent upon the convergence of these two pathways in a dose-dependent manner. The work of Okubo and Hogan highlights the plasticity of tissue-specific precursors when the dose of certain signalling molecules is altered within the developing endoderm and lends further support to the potential of manipulating such signalling pathways in stem cells for cellular replacement therapies in conditions such as diabetes and metabolic liver disease.

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