On Oct. 19, 2020, researchers announced they had discovered that a gene, called PIEZO2, may be responsible for the powerful urge to urinate that we normally feel several times a day. The results, published in Nature, suggest that the gene helps at least two different types of cells in the body sense when our bladders are full and need to be emptied. These results also expanded the growing list of newly discovered senses under the gene’s control.

Urine is produced when the kidneys extract waste and excess water from the blood and send it to the bladder. Over time, it fills up and expands like a balloon, putting tension on the bladder muscles. Then, at a certain point, the body senses that it is reaching a limit, which triggers the urge to urinate.

The PIEZO2 gene contains instructions for making proteins that are activated when cells are stretched or squeezed. In this study, the researchers found that patients who are born with a genetic deficiency in PIEZO2 have trouble sensing bladder filling while experiments in mice suggested the gene plays two critical roles in this process. It may help certain bladder cells gauge expansion while also sparking neurons to relay tension signals to the rest of the nervous system.

The study was a collaboration between Dr. Patapoutian’s team and researchers working in NIH labs led by Alex Chesler, Ph.D., senior investigator, at the NIH’s National Center for Complementary and Integrative Health (NCCIH) and a senior author of the paper, and Carsten Bönnemann, M.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

In 2010, Dr. Patapoutian’s team discovered the PIEZO2 gene along with a similar gene called PIEZO1 in a line of mouse brain tumors. Before then, scientists knew of only a few rare examples from flies, worms, and mice in which a gene helped tissue, such as hairy skin cells, sense changes in shape and pressure. Since the discovery, Dr. Patapoutian’s team and others have primarily shown in mice that the PIEZO2 gene may play many roles throughout the body including controlling the sense of touch, vibration, pain, and proprioception, the unconscious awareness of one’s body in space.

Initially, the researchers found that the PIEZO2 gene was highly active in a few dorsal root ganglion (DRG) neurons that send nerve signals from the mouse bladder to the brain. Aided by an advanced, real-time imaging system, they saw that the cells lit up with activity when a mouse’s bladder filled with fluid. They also found that the PIEZO2 gene was turned on in some “umbrella” cells which are found among the cells that line the inside of a bladder.

Next, they found that deleting the gene from the neurons and umbrella cells not only reduced the cells’ responses to bladder filling but also caused the mice to have problems with urination. The mutant mice showed some signs of incontinence and urinated randomly in their cages instead of in a corner as seen with control mice. Meanwhile, mutant mouse bladders required more fluid and greater pressure than normal to trigger urination which was reminiscent of the patient reports. They also found that deleting the gene from the two cell types had longer lasting effects. For instance, the muscles of the mutant bladders were thicker than controls, suggesting the loss of sensation remodeled the bladder.

Finally, the researchers found that deleting the PIEZO2 gene from either the umbrella cells or the DRG neurons produced similar results as deleting it from both cell types simultaneously. Eliminating the gene from either cell lengthened the time that mice would take before feeling the need to squeeze their bladders and it increased the pressure applied during each squeeze.

In the future, the researchers will continue to examine the role PIEZO2 plays in urination and other interoceptive senses while also exploring the clinical implications of their discovery for the millions suffering from urinatory control problems.