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bioRxiv · 10.64898/2026.09.16.752084

A discrete Connexin26+ neural crest lineage emerges in mid-life and mediates enhanced central brainstem responses to elevated CO2 levels for deep breathing.

Zhang, X.·Zhang, J.·Lapage, J. M. J.·Gourine, A. V.·Dale, N.·Koentges, G.
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Abstract

The precise control of breathing is fundamental to vertebrate survival. Increased PCO2 in blood and brain parenchyma causes an increase in both the frequency and volume of lung ventilation. We have previously demonstrated that CO2 directly binds to connexin26 (Cx26) hemichannels causing them to open and allow release ATP. We now document the role of Cx26 as a direct physiological CO2 sensor in vivo. Here we describe a unique Cx26+ neural crest cell lineage that populates the ventral brainstem in the vicinity of the PreBoetz nucleus/caudal CO2 chemosensory area during middle age and dies again in old age. Ablating Cx26 genetically specifically within this population of about 20 cells by two independent neural crest Cre-driver lines leads to a loss of local ATP release in the posterior chemosensory area as well as a 40% reduction in elevated tidal volume responses specifically in middle age, as measured by whole-body plethysmography. These in vivo effects change over a life-time: they directly mirror the arrival, wiring in middle age and later death of this cell population in old age. This is a first known example of a middle age change in cranial neural crest lineage composition and highlights the significant power of very few cells for global metabolism. Such lineage-dependent middle-age dynamics also impacts upon the evolution of eusociality: altricial naked pups of our common amniote/synapsid ancestors were heated by by the breath of their (middle-aged) carers, sensing elevated CO2 levels in hypercapnic burrows. Such mechanistic exaptation enabled small amniotes to sense and survive the lethal global CO2 spikes during the Permo-Triassic and other extinction events.

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Zhang, X., Zhang, J., Lapage, J. M. J., Gourine, A. V., Dale, N., Koentges, G.. 2026-09-21. A discrete Connexin26+ neural crest lineage emerges in mid-life and mediates enhanced central brainstem responses to elevated CO2 levels for deep breathing.. https://doi.org/10.64898/2026.09.16.752084

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