Journal
BMC BIOLOGY
Volume 12, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s12915-014-0092-2
Keywords
Airway branching; Lung morphogenesis; Lung development; Tracheal branching; Trachea development; Innervation; Denervation; Neurotransmission; Parasympathetic; Laser ablation
Categories
Funding
- NIH NHLBI NRSA [1F30 HL110723-01]
- NIH FaceBase grant [U01 DE020063]
- Pasadena Guild of Children's Hospital Los Angeles
- NIH HL LungMAP grant [44060, 44977, 60231]
- Garland Foundation
- Webb Foundation
- Santa Anita Guild Endowment
- Pasadena Guild Endowment of Children's Hospital Los Angeles
- MRC New Investigator Award
- MRC Centenary Award
- American Asthma Foundation Early Excellence Award
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [F30HL110723] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [U01DE020063] Funding Source: NIH RePORTER
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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.
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