Developmental Cell
Volume 57, Issue 13, 11 July 2022, Pages 1566-1581.e7
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Article
A functional circuit formed by the autonomic nerves and myofibroblasts controls mammalian alveolar formation for gas exchange

https://doi.org/10.1016/j.devcel.2022.05.021Get rights and content
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Highlights

  • Mouse lung air sacs are innervated by autonomic nerves during alveolar development

  • VANGL2 regulates neurotransmitter release from autonomic nerves to control alveologenesis

  • Alveolar myofibroblasts are a target of autonomic innervation during secondary septation

  • Alveolar myofibroblasts secrete neurotrophins to regulate autonomic nerve function

Summary

Alveolar formation increases the surface area for gas exchange. A molecular understanding of alveologenesis remains incomplete. Here, we show that the autonomic nerve and alveolar myofibroblast form a functional unit in mice. Myofibroblasts secrete neurotrophins to promote neurite extension/survival, whereas neurotransmitters released from autonomic terminals are necessary for myofibroblast proliferation and migration, a key step in alveologenesis. This establishes a functional link between autonomic innervation and alveolar formation. We also discover that planar cell polarity (PCP) signaling employs a Wnt-Fz/Ror-Vangl cascade to regulate the cytoskeleton and neurotransmitter trafficking/release from the terminals of autonomic nerves. This represents a new aspect of PCP signaling in conferring cellular properties. Together, these studies offer molecular insight into how autonomic activity controls alveolar formation. Our work also illustrates the fundamental principle of how two tissues (e.g., nerves and lungs) interact to build alveoli at the organismal level.

Keywords

alveolar formation
gas exchange
autonomic nerves
neurotrophins
neurotransmitters
myofibroblasts
planar cell polarity signaling
proliferation
chronic obstructive lung disease
contraction/migration

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