Freem, L.J.; (2011) The development of the neural crest-derived intrinsic innervation of the lung. Doctoral thesis , UCL (University College London).

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Abstract

The autonomic airway ganglia that comprise the intrinsic lung innervation are derived from vagal neural crest cells (NCC) that migrate tangentially from the foregut into the embryonic lung buds. The aim of this PhD thesis was to investigate the mechanisms that direct NCC from the foregut into the lungs and that subsequently influence their development. A novel combination of cell labelling, using Wnt1Cre:Rosa26YFP double transgenic reporter mice, and Optical Projection Tomography (OPT) imaging was employed to visualize lung innervation. Results showed that NCC migrated into the lungs from the esophagus early in development, accumulated around the epithelial tubules and differentiated into an extensive network of neurons and glial cells. Next, chick intraspecies grafting was used to test the developmental potential of lung and gut NCC. Results showed that when NCC from the gut were back-grafted into the early migration pathway these cells colonised both the lungs and gut, indicating that vagal NCC are not prespecified to colonise either organ and are thus likely to respond to common signalling cues. When potential cues were tested in organotypic lung culture, NCC migrated towards sources of the RET (Rearranged during Transfection) ligand GDNF (Glial-cell-line-derived neurotrophic factor), suggesting that the RET signalling pathway is involved in NCC colonisation of the lung. However, examination of RET mutants indicated that this pathway is not necessary for NCC colonisation of the lung, since lung innervation in Ret-/- mouse embryos was similar to controls. Lung innervation was further examined in several mouse mutants with known NCC defects. Intrinsic ganglia formation was altered in Sox10Dom and Tbx1 mutant mouse lungs, implicating a role for vagal nerve projections in guiding NCC within the lung. Together these studies have described the development of intrinsic lung innervation in the avian and mammal and examined multiple mechanisms underlying NCC development within the lung.

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