Dysfunctional neural control of airway smooth muscle (ASM) is involved in inflammatory diseases, such as asthma. However, neurogenesis in the lung is poorly understood. This study uses mouse models to investigate developmental mechanisms of ASM innervation, a process that is highly coordinated with ASM formation during lung branching morphogenesis. We show that brain-derived neurotrophic factor (BDNF) is an essential ASM-derived signal for innervation. Although BDNF mRNA expression is temporally dissociated with ASM formation and innervation, BDNF protein is coordinately produced through post-transcriptional suppression by miR-206. Using a combination of chemical and genetic approaches to modulate sonic hedgehog (Shh) signaling, a pathway essential for lung branching and ASM formation, we show that Shh signaling blocks miR-206 expression, which in turn increases BDNF protein expression. Together, our work uncovers a functional cascade that involves Shh, miR-206 and BDNF to coordinate ASM formation and innervation.

Our study investigates the innervation of the respiratory tract during mouse embryonic development, with a focus on the identification of cell origin and essential developmental signals for the resident, or intrinsic, neurons. Using lineage tracing, we show that these intrinsic neurons are exclusively derived from neural crest cells, and cluster to form ganglia that reside in the dorsal trachea and medial bronchi with diminishing frequency. Comparisons of intrinsic neurogenesis between wild-type, glial cell-derived neurotrophic factor (GDNF) 2/2 , neurturin 2/2 , and tyrosine kinase receptor Ret 2/2 embryos, in combination with lung organ cultures, identified that Ret signaling, redundantly activated by GDNF family members, is required for intrinsic neurogenesis in the trachea and primary bronchi. In contrast, Ret deficiency exerts no effect on the innervation of the rest of the respiratory tract, suggesting that innervation by neurons whose cell bodies are located outside of the lung (so-called extrinsic neurons) is independent of Ret signaling. Furthermore, although the trachea, the esophagus, and their intrinsic neurons share foregut endoderm and a neural crest cell origin, respectively, the signals required for their intrinsic neurogenesis are divergent. Together, our results not only establish the neural crest lineage of intrinsic neurons in the respiratory tract, but also identify regional differences in the abundance and developmental signals of intrinsic neurons along the respiratory tract and in the esophagus.

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