The role of fibroblast growth factor receptor 2b signalling on distal epithelium during embryonic and pseudoglandular stage murine lung development

Murine lung development depends on an intricate interplay of molecular, cellular, and physical factors. An active area of research is on molecular signalling between the mesenchyme and adjacent airway epithelium. One such pathway involves fibroblast growth factors (FGFs), secreted in the distal mesenchyme, binding to fibroblast growth factor receptor 2b (FGFR2b) on adjacent epithelium. The primary FGF during early lung development is FGF10. In mouse models where either Fgf10 or Fgfr2b was constitutively knocked-out, complete lung agenesis was observed. However, nearly 25 years from these original observations, little is known concerning the direct transcriptional and biological targets of FGFR2b signalling during lung development. Our research has begun to address this lack of knowledge. Using conditional in vivo mouse models to globally inhibit FGFR2b ligands or inactivate Fgfr2b gene expression in target cells, we addressed the broad roles played by FGFR2b signalling throughout embryonic (embryonic day I 9.5-E10.5), early pseudoglandular (E10.5-E12.5), mid-pseudoglandular (E14.5), and late pseudoglandular stage (E16.5) lung development in mice. We had three main aims: 1) to characterize the biological impacts and identify transcriptional signatures of FGFR2b signalling during these stages of development; 2) to assess the role played by FGFR2b signalling on alveolar lineage formation and differentiation; and 3) to use the gene signatures obtained from ‘aim 1’ to identify, in silico, populations of cells responding to FGFR2b signalling during development, homeostasis, and repair after injury. Results indicate that FGFR2b signalling regulates lobar septation and accessory lobe formation during embryonic stage lung development; branching morphogenesis and cellular proliferation during early- and mid-pseudoglandular stage development; and alveolar lineage specification and differentiation from the late pseudoglandular stage. Interestingly, data suggest that during early alveolar lineage formation, where alveolar type 1 and 2 (AT1 and AT2) progenitors are specified, FGFR2b signalling prevents progenitors from committing to the opposing lineage. Finally, in silico data mining revealed that the gene signatures from E12.5, E14.5, and E16.5., converged on a subpopulation of AT2 cells during late lung development and homeostasis. Upon repair after injury, these signatures were effectively lost in AT2 cells transitioning to AT1 cells; this supports the finding that FGFR2b is required to prevent alveolar cross-lineage transdifferentiation. The results reported in this thesis offer a broad foundation for future work on the role of FGFR2b signalling during lung development. We have provided sets of target genes at multiple embryonic timepoints, which can form the basis for more exhaustive investigation. Furthermore, we have presented compelling evidence for a novel interpretation of FGFR2b signalling on the lineage-commitment of alveolar progenitor cells. Specifically, that FGFR2b signalling prevents alveolar progenitors from committing to the opposing lineage. Finally, our in silico results support an increasingly appreciated fact in the field of lung development, namely, that populations of cells are extremely heterogenous. Accurately classifying a population of interest is critical for effective hypothesis formulation, experimental design, and interpretation of results.

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The role of fibroblast growth factor receptor 2b signalling on distal epithelium during embryonic and pseudoglandular stage murine lung development

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