Brain Development and the Role of RNA modification

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Human forebrain organoid labeled with Green Fluorescent Protein (green), neural stem cell marker SOX2 (red) and cell nuclei marker (blue). Credit: Xuyu Qian and Guo-li Ming, Perelman School of Medicine, University of Pennsylvania

A chemical tag added to RNA during embryonic development regulates how the early brain grows.

In the last few years, scientists have discovered chemical modifications to messenger RNA (mRNA) across the genome at certain sites and found that these changes are dynamic, meaning that a specific chemical group is added and taken off by enzymes in a regular, patterned way. The chemical group [..], m6A, is the most prevalent modification to mRNA in human cells.
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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 born out of this knowledge.

[..] 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. Ming and Song surmise that this is 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.

According to the Scientists:

"We used an organoid, a mini-brain, made from human induced pluripotent stem cells to relate the mouse knockout findings to humans," Neuroscience professors Guo-li Ming, MD, PhD, said. "m6A signaling also regulates neuron development in human forebrain organoids."

Neuron development in the mini-brains that Ming has developed is similar to what happens in people, modeling fetal brain development up to the second trimester.

"We were surprised when we found that human stem cells had a greater number of m6A tags compared to mouse cells," Ming said. "Comparing the m6A-mRNA landscapes between mouse and human embryonic brain development showed us that human-specific m6A-tagging might be related to brain-disorder risk genes."
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News Reference Medical Xpress

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