A study published in the journal Neuron has found that neurons are intrinsically programmed for continuous survival during development. According to researchers from the University of California, Riverside, a mechanism has been identified which is believed to be triggered at neuron birth to intrinsically reduce apoptosis—a form of cell death.

However, when this genetic regulation is obstructed, the continuous survival of neurons is disrupted, which ultimately leads to the death of the animal. Sika Zheng, the lead author of the study, said in a statement, "We show neurons transform how they regulate cell death during development."

Redefining Notions

NEURONS
Neurons created from chemically-induced neural stem cells Mingliang Zhang, PhD, Gladstone Institutes

Most neurons are created during embryonic development and have no "backup" after birth. Researchers have generally believed that their survival is determined nearly extrinsically, or by outside forces, such as the tissues and cells that neurons supply with nerve cells.

The research team has challenged this notion and reported that the continued survival of neurons is also intrinsically programmed during development. An organism's survival, brain function, and fitness are dependent upon the survival of its neurons. In higher organisms, neurons control breathing, feeding, sensation, motion, memory, emotion, and cognition.

They can die of many unnatural causes, such as neurodegenerative diseases, injury, infection, and trauma. Neurons are long-lived cells, but the genetic controls that enable their longevity are unknown.

Crucial Section of the Mechanism

Zheng's team now reports the central piece of the mechanism involved is a small piece of genetic sequence in Bak1, a pro-apoptotic gene whose activation leads to apoptosis. Bak1 expression is turned off when this small piece of genetic sequence, termed microexon, is spliced in the final Bak1 gene product. Exons are sequences that makeup messenger RNA.

"Apoptosis is a pathway that controls cell turnover and tissue homeostasis in all metazoans," explained Zheng, an associate professor of biomedical sciences. "Most non-neural cells readily engage in apoptosis in response to intrinsic and extrinsic stress. But this cellular suicidal program needs to be reined in for neurons so that they live for many years. We now show how genetic attenuation of neuronal apoptosis takes place."

Reduced Sensitivity to Cell Death

Zheng's team identified the Bak1 microexon through large-scale analysis of expression data from human tissues, mouse tissues, human developing brains, mouse developing forebrains, and mouse developing midbrains. The team first compared neural tissues with non-neural tissues in both humans and mice to identify neural-specific exons.

Then, they found cortical neurons reduce their sensitivity to apoptosis as early as neuron birth. They also found apoptosis is gradually reduced during neuronal development before neurons make connections or innervate other cells, suggesting factors other than extrinsic signals can play a role.

Zheng added, "This is to ensure neuronal longevity, which is needed to maintain the integrity of neural circuits for brain functions." Next, Zheng's team will study whether the identified mechanism is activated in neurodegenerative diseases and injury that cause neuronal cell death.

(With inputs from agencies)