RNA modification and brain development

A chemical tag added to RNA during embryonic development regulates how the early brain grows, when this development goes wrong, it may cause psychiatric disorders in people. Researchers used animal models and mini-brains, made from human stem cells to relate their findings to conditions found in people.

Researchers have discovered chemical modifications to messenger RNA mRNA across the genome at certain sites and found that these changes are dynamic- a specific chemical group is added and taken off by enzymes in a regular, pattern. The chemical group studied in the Cell paper, m6A, is the most prevalent modification to mRNA in human cells.

The current thinking is that a tightly controlled molecular process guides the complicated development of the brain before birth and the process relies on a precise sequence of genes being turned on and off. However, even subtle mistakes in this process can become serious issue. The classic view of this control is that DNA codes for RNA, guiding which proteins will be made by cells. However, mRNA can be modified along the way so that it can produce proteins with many variations.

A new field called epitranscriptomics was discovered during the research. The Cell paper is the first study of epitranscriptomics in the embryonic mammalian brain, and the key is m6A, a marker for molecules bound for disposal within the cell. Normally, m6A-tagged mRNAs are related to such processes as cell replication and neuron differentiation, and m6A-tagging promotes their decay after they are no longer needed.

If m6A is not added on the correct time schedule to a garbage-bound molecule, the developmental train goes down the wrong tracks because developing brain cells get stuck at an earlier stage because the m6A cues for taking out the cellular trash are misread or not read at all. The researchers found that in a mouse model with depleted m6A, cell replication is prolonged, so that stem-cell differentiation, which normally reels out daughter cells in an orderly fashion, gets stuck. The knockout mouse develops less brain cells such as neurons and glia cells, and therefore has abnormal circuitry and a non-functioning brain.

Neuron development in the mini-brains that was developed is similar to what happens in people, modeling fetal brain development up to the second trimester. Human stem cells had a greater number of m6A tags compared to mouse cells. Many of the genes associated with genetic risk for certain conditions, such as schizophrenia and autism spectrum disorder, are only m6A-tagged in humans, not in mice, raising the possibility that dysregulation at this level of gene expression may contribute to certain human brain disorders.
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