An analysis of more than 2,300 individual nerve cells suggests that the developing human brain organizes itself before and after birth by eliminating large numbers of neurons carrying genetic abnormalities. The study found that more than one-quarter of neurons sampled from fetal brains had gained or lost portions of their chromosomes, compared with about 6% of neurons in brains after birth.
The analysis, published in Nature on October 28, found that the proportion of neurons with these abnormalities fell by more than fourfold after birth. “This suggests that the neurons that survived may be the ones that had the most intact genomes during development,” says Christos Proukakis, a neurologist at University College London who was not involved in the study.
Diane Hsiao, a pediatric neurogeneticist at Boston Children’s Hospital in Massachusetts and the paper’s lead author, says the findings reveal a previously unknown mechanism that helps regulate the number of neurons in the brain and determine which fetal neurons survive.
Understanding this process could help researchers investigate neurological conditions that commonly emerge during childhood, including autism spectrum disorder (ASD) and epilepsy.
A form of cellular quality control
Research in mice suggests that mammals eliminate many brain cells early in development by activating molecular programs that trigger cell death. To examine whether a similar process occurs in humans, Hsiao and her colleagues studied brain tissue from deceased individuals ranging from fetuses as young as 14 weeks to people in their 90s. The researchers focused on neurons in the cerebral cortex, which is involved in functions including memory, learning and consciousness.
They analyzed the genomes of individual neurons for copy-number variations—segments of chromosomes that have been gained or lost. The researchers found a surprisingly large number of neurons with a broad range of these variations during fetal development.
The results were so unexpected that Hsiao and her colleagues spent years testing whether the findings were genuine. However, they obtained similar results when they repeated the experiments using different single-cell sequencing methods.
After birth, the proportion of neurons with abnormal copy-number variations declined sharply, suggesting that many of these cells are eliminated during development.
It remains unclear how the brain distinguishes between normal and abnormal neurons. One possible clue, Hsiao says, is that neurons with high levels of copy-number variation tend to show unusual activity in genes involved in forming synapses, the connections between neurons.
Source: www.nature.com