A team led by scientists identified a molecule called microRNA-29 as a powerful controller of brain maturation in mammals. Deleting microRNA-29 in mice caused problems very similar to those seen in autism, epilepsy, and other neurodevelopmental conditions.
The researchers examined a mouse model in which the genes for the miR-29 family were deleted just in the brain. They observed that although the mice were born normally, they soon developed a mix of problems, including repetitive behaviors, hyperactivity, and other abnormalities typically seen in mouse models of autism and other neurodevelopmental disorders. Many developed severe epileptic seizures.
To get a sense of what caused these abnormalities, the researchers examined gene activity in the brains of the mice, comparing it to activity in mouse brains that had miR-29. Many genes were much more active when miR-29 was no longer there to block their activity. But the scientists unexpectedly found a large set of genes—associated with brain cells—that were less active in miR-29's absence.
One of the target genes that miR-29 normally blocks is a gene that encodes for an enzyme called DNMT3A. This enzyme places special chemical modifications called CH-methylations onto DNA, to silence genes in the vicinity. In mice brains, the activity of the gene for DNMT3A normally rises at birth and then sharply declines several weeks later.
Thus, in the mice whose brains lack miR-29, DNMT3A is not suppressed and the CH-methylation process continues abnormally—and many brain cell genes that should become active continue to be suppressed instead. Some of these genes, and the gene for DNMT3A itself, have been found to be missing or mutated in individuals with neurodevelopmental disorders such as autism, epilepsy, and schizophrenia.
"We think abnormalities in microRNA-29 activity are likely to be a common theme in neurodevelopmental disorders and even in ordinary behavioral differences in individuals," said the senior author. "Our work suggests that boosting levels of miR-29, perhaps even by delivering it directly, could lead to a therapeutic strategy for neurodevelopmental disorders such as autism."
Source: DOI: 10.1016/j.celrep.2021.108946