The Onset of Breathing at Birth Switches Off Regenerative Capacity
Year: 2026
Type: preprint
Abstract: Many mammalian tissues, including the central nervous system (CNS), lose regenerative capacity in adulthood1-3, but when and how this transition is initiated remains unclear. By monitoring mTOR activity, an evolutionarily conserved readout of cellular growth and intrinsic regenerative potential4-11, we found that mTOR signaling declines within minutes after birth in murine CNS neurons and in other organs such as the heart and skeletal muscles. Focusing on retinal ganglion cells (RGCs), we show that this abrupt decline is driven primarily by CO₂ exhalation following the onset of breathing after birth. Using real-time in vivo imaging of RGCs during the earliest postnatal period, we further discover that breathing-induced CO₂ exhalation rapidly causes intracellular alkalinization, activates an AMPK-family kinase, SNF-related kinase (SNRK)12-14, which in turn suppresses mTOR signaling. Importantly, this process remains reversible in adulthood: CO₂ inhalation or Snrk deletion restores mTOR activity in RGCs and enables robust regeneration of their axons after injury. Similar CO₂ inhalation-induced mTOR reactivation occurs across multiple cell types and organs, suggesting a general mechanism by which breathing-associated CO₂/pH signaling shapes the regenerative capacity across life and pointing to a potential CO₂-based strategy for promoting tissue regeneration.
Authors: Xuan Song, Xinyi Cai, Shane V. Hegarty, Davide Speri, Masahiro Yasuda, Ryan J. Donahue, Joanna Stanicka, Ting Yan, Susu Mao, Sarah Yang, Jiawen Chen, Junjie Zhu, James K. Kiraly, Cheng-Hao Chien, Evgenii Kegeles, Daniel Feng, Kevin C. Stieger, Zhiyun Yang, Yiming Zhang, Gary Yellen, Hisashi Umemori, Philip R. Williams, Zhigang He
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221473300