A functional circuit formed by the autonomic nerves and myofibroblasts controls mammalian alveolar formation for gas exchange

• Published in: Developmental cell 2022-07, Vol.57 (13), p.1566-1581.e7
• Main Authors: Zhang, Kuan, Yao, Erica, Wang, Shao-An, Chuang, Ethan, Wong, Julia, Minichiello, Liliana, Schroeder, Andrew, Eckalbar, Walter, Wolters, Paul J., Chuang, Pao-Tien
• Format: Article
• Language: English
• Subjects: alveolar formation; Animals; autonomic nerves; Autonomic Pathways; chronic obstructive lung disease; contraction/migration; gas exchange; Lung; Mammals; Mice; Myofibroblasts; neurotransmitters; neurotrophins; Organogenesis; planar cell polarity signaling; proliferation; Pulmonary Alveoli
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2022.05.021

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. [Display omitted] •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 Zhang et al. demonstrate that autonomic nerves and alveolar myofibroblasts form a functional unit during alveolar formation. These nerves secrete neurotransmitters to promote proliferation, contraction, and migration of alveolar myofibroblasts for proper secondary septation. Alveolar myofibroblasts secrete neurotrophins to affect autonomic nerve function.