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Published November 11, 2014 | Published + Supplemental Material
Journal Article Open

Airway branching has conserved needs for local parasympathetic innervation but not neurotransmission


Background: Parasympathetic signaling has been inferred to regulate epithelial branching as well as organ regeneration and tumor development. However, the relative contribution of local nerve contact versus secreted signals remains unclear. Here, we show a conserved (vertebrates to invertebrates) requirement for intact local nerves in airway branching, persisting even when cholinergic neurotransmission is blocked. Results: In the vertebrate lung, deleting enhanced green fluorescent protein (eGFP)-labeled intrinsic neurons using a two-photon laser leaves adjacent cells intact, but abolishes branching. Branching is unaffected by similar laser power delivered to the immediately adjacent non-neural mesodermal tissue, by blocking cholinergic receptors or by blocking synaptic transmission with botulinum toxin A. Because adjacent vasculature and epithelial proliferation also contribute to branching in the vertebrate lung, the direct dependence on nerves for airway branching was tested by deleting neurons in Drosophila embryos. A specific deletion of neurons in the Drosophila embryo by driving cell-autonomous RicinA under the pan-neuronal elav enhancer perturbed Drosophila airway development. This system confirmed that even in the absence of a vasculature or epithelial proliferation, airway branching is still disrupted by neural lesioning. Conclusions: Together, this shows that airway morphogenesis requires local innervation in vertebrates and invertebrates, yet neurotransmission is dispensable. The need for innervation persists in the fly, wherein adjacent vasculature and epithelial proliferation are absent. Our novel, targeted laser ablation technique permitted the local function of parasympathetic innervation to be distinguished from neurotransmission.

Additional Information

© 2014 Bower et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Received: 17 August 2014; Accepted: 20 October 2014; Published: 11 November 2014. DVB was funded by NIH NHLBI NRSA 1F30 HL110723-01, NIH FaceBase grant #U01 DE020063 and the Pasadena Guild of Children's Hospital Los Angeles. DW was funded by NIH HL LungMAP grant, 44060, 44977, 60231, the Garland Foundation, the Webb Foundation, the Santa Anita Guild Endowment and the Pasadena Guild Endowment of Children's Hospital Los Angeles. ECJ was funded by a MRC New Investigator Award, a MRC Centenary Award and an American Asthma Foundation Early Excellence Award. Authors' contributions: ECJ conceived the overall study. DVB and ECJ designed the experiments with RL, DW and SEF. DVB developed the laser ablation technique with ECJ and SEF and conducted the lung culture studies with support from ECJ, RL and DW. DVB performed the Drosophila studies with support from HKL, ECJ and KZ. ECJ and DVB wrote the manuscript. DVB realised the figures. All authors reviewed and redrafted the manuscript as necessary. All authors read and approved the final manuscript. The authors declare that they have no competing interests.

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Supplemental Material - FigureS1.tiff

Supplemental Material - TableS1.doc


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