With every breath

Most of us do not spend much time thinking about breathing (now you are :D). This is because our autonomic nervous system hides its control under our consciousness. But, breathing is not as effortless as it seems. For one, air pressure and oxygen level can change from time to time. Also, diseases such as the common flu often disturb the flow of our airways. For reasons like these, we often have to modulate the rate and depth of our breaths. Therefore, a pre-programmed breathing rhythm does not suffice –breathing also requires constant monitoring and feedback.

Nonomura and Woo et al1 from the Patapoutian lab study the mechanosensation that happens during breathing. They started by identifying the sensor protein that detect lung inflation: Piezo2. The Patapoutian lab has previously shown that the Piezo family proteins are a group of ion channels that are likely force sensors2 in the fly3 and in the mammalian skin4,5. When Nonomura and colleagues removed the piezo2 gene from the mouse genome, the newborn pups have trouble breathing and die within the first 24 hours after birth. Postmortem examinations show that the Piezo2 knockout mice have less airspace in their lungs, a sign of failed lung inflations. The same phenotypes – failure in lung inflation and early lethality – are also observed when piezo2 is knocked out by a cre recombinase expressed in spinal sensory neurons (often referred to as the DRG neurons), suggesting that Piezo2 signaling through the spinal cord is required for proper breathing in newborn mice.

The spinal cord sensory neurons, however, are not the only neurons known to innervate the lung. Sensory neurons in the vagus nerve (the 10th cranial nerve) also project to the lung. What is their function? Nonomura and Woo et al found that, although knocking out piezo2 from the vagal neurons do not lead to early lethality, stimulating these neurons does temporarily stop mice from breathing. It turns out that these vagal neurons play a more nuanced role in controlling breathing. Knocking out piezo2 from the vagal neurons causes mice to breathe deeper. This is likely because the vagal neurons are no longer able to sense the lung stretching, as responses in vagal nerve activity to increased air flow is drastically decreased in piezo2 knockout mice. Therefore, since piezo2-mutant vagal sensory neurons have trouble sensing how much the lung has stretched, they have trouble telling the lung to stop inflating, causing the animals to breathe deeper. Since deep breaths are a relatively mild phenotype, these mice can survive well after birth.

These findings provide us with insight into why patients with distal arthrogryposis type 5 (DA5) sometimes develop lung diseases in addition to, and perhaps independent of, the typical joint contractures. Some of the patients carry a dominant mutation in the piezo2 gene that produces channels with slower inactivation6. In the vagal sensory neurons, these hyperactive channels can lead to over-inflating the lung, thereby causing secondary lung complications.

References

1. Nonomura, K. et al. Piezo2 senses airway stretch and mediates lung inflation-induced apnoea. Nature 541, 176–181 (2017).

2. Coste, B. et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330, 55–60 (2010).

3. Kim, S. E., Coste, B., Chadha, A., Cook, B. & Patapoutian, A. The role of Drosophila Piezo in mechanical nociception. Nature 483, 209–212 (2012).

4. Woo, S.-H. et al. Piezo2 is required for Merkel-cell mechanotransduction. Nature 509, 622–626 (2014).

5. Ranade, S. S. et al. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516, 121–125 (2014).

6. Coste, B. et al. Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis. Proc. Natl. Acad. Sci. U. S. A. 110, 4667–72 (2013).