A team led by scientists from the UNC School of Medicine identified a molecule called microRNA-29 as a powerful controller of brain maturation in mammals. Deletion of microRNA-29 in mice caused problems very similar to those seen in autism, epilepsy, and other neurodevelopmental conditions.
Results published in Cell reports, shed light on an important process in normal brain maturation and suggest the possibility that disruption of this process could contribute to multiple diseases of the human brain.
We think that abnormalities in microRNA-29 activity are likely to be a common topic in neurodevelopmental disorders, and even in common behavioral differences in individuals. Our work suggests that elevated miR-29 levels, perhaps even by direct delivery, could lead to therapeutic therapy. strategy for neurodevelopmental disorders such as autism. “
Dr. Mohanish Deshmukh, Senior Study Author and Professor, Department of Cell Biology and Physiology, University of North Carolina
Deshmukh is also a member of the UNC Center for Neuroscience.
miR-29 and brain maturation
MicroRNAs are short portions of ribonucleic acid within cells that regulate gene expression. Any microRNA or miR can directly bind to an RNA transcript from certain other genes, preventing it from being translated into a protein.
MiRNAs thus effectively serve as inhibitors of gene activity, and typical microRNAs thus regulate multiple genes so that genetic information is not over-expressed. These basic regulators have been intensively researched only in the last two decades. Therefore, much more needs to be revealed about their role in health and disease.
Deshmukh and colleagues set out to find the microRNAs involved in brain maturation after birth, a phase that involves humans in about the first 20 years of life.
When scientists searched for microRNAs with more activity in the brain of an adult mouse than the brain of a young mouse, one set of miRNAs lagged behind the rest. Levels of the miR-29 family were 50 to 70 times higher in the brains of adult mice than in the brains of young mice.
The researchers examined a mouse model in which the genes of the miR-29 family were deleted in the brain. They noted that although mice were born normal, they soon developed a combination of problems, including repetitive behaviors, hyperactivity, and other abnormalities typical of mouse models of autism and other neurodevelopmental disorders. Many have developed severe epileptic seizures.
To gain insight into what caused these abnormalities, the researchers examined gene activity in the brains of mice, comparing it to the activity in the brains of mice that had miR-29.
As expected, many genes were much more active when miR-29 was no longer there to block their activity. But scientists have unexpectedly found a large set of genes – linked to brain cells – that are less active in the absence of miR-29.
With the key help of the co-author, dr. Michael Greenberg, a professor of neuroscience at Harvard University, the researchers eventually found an explanation for this mysterious decrease in gene activity.
One of the target genes that miR-29 normally blocks is a gene that encodes an enzyme called DNMT3A. This enzyme puts special DNA chemical modifications called CH-methylations to silence nearby genes. In the brain of mice, the activity of the DNMT3A gene usually increases at birth and then decreases sharply a few weeks later. Scientists have discovered that miR-29, which blocks DNMT3A, is what usually forces this sudden drop.
Thus, in mice lacking miR-29 in the brain, DNMT3A is not suppressed and the CH-methylation process continues abnormally – and many brain cell genes that should become active are still suppressed. Some of these genes, like the DNMT3A gene itself, have been found to be missing or mutated in individuals with neurological developmental disorders such as autism, epilepsy, and schizophrenia.
To confirm the role of DNMT3A, the scientists created a unique mouse model that prevents miR-29 from suppressing DNMT3A but leaves other targets of miR-29 intact. They showed that this release of DNMT3A in itself results in many of the same problems as seizures and early death, as seen in mice without miR-29.
The findings highlight and clarify what appears to be a likely key process in brain development in late development: the exclusion of DNMT3A to release many genes thought to be more active in the adult brain.
“These results are the first to identify miR-29 as the primary regulator of CH methylation and show why limiting CH methylation to a critical period is important for normal brain maturation,” Deshmukh said.
Deshmukh and colleagues are now following a more detailed study of how miR-29 deficiency in different groups of brain cells could lead to such disorders, and more generally studying how miR-29 activity is regulated in childhood by tuning brain functions, giving people traits that make them unique individuals.
University of North Carolina School of Medicine
Swahari, V., and others. (2021) MicroRNA-29 is an essential regulator of brain maturation through the regulation of CH methylation. Cell reports. doi.org/10.1016/j.celrep.2021.108946.