NYSCF Innovators Explore How Methylation Affects Motor Neuron Development

Before a motor neuron can become a motor neuron, it has to undergo some important changes. One of these changes happens through a process called methylation. In methylation, a methyl group (a group of one carbon and three hydrogen atoms) attaches to DNA and alters its function. In a recent study, NYSCF – Robertson Investigator Alumnus Alexander Meissner, PhD, of Harvard University teamed up with NYSCF – Druckenmiller Fellow Alumnus Evangelos Kiskinis, PhD, of Northwestern University to investigate how methylation guides stem cells into motor neurons.

For methylation to take place, our bodies need the help of enzymes called methyltransferases. The researchers were first interested in how neural cells would differentiate in the absence of a certain methyltransferase called DNMT3A. To explore this question, they generated neural cells from embryonic stem cells and then removed DNMT3A from the cellular environment.

Instead of developing into motor neurons like they usually would, most cells instead differentiated into a type of glial cell called a floor plate cell. The few cells that did differentiate into motor neurons showed functional defects in their dendrites and altered electrophysiological properties.

Next, the team was interested in whether these defects could be corrected for by restoring methylation at certain genomic locations. They targeted the PAX6/ARX gene and found that selective methylation rescued the motor neurons from dysfunction.

These results shed light on how methylation affects motor neuron development and lay the framework for future studies on how methylation dynamics determine cellular fate. For more info, check out the paper in Cell Stem Cell.