Lack of Enzyme Crimps Movement Nerve Cell Development, Study Suggests

Lack of an enzyme prevents movement nerve cells from developing properly, suggesting that the shortage may play a role in ALS, a Northwestern University study reports.

The study in the journal Cell Stem Cell was titled “Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology.”

A chemical modification of DNA known as DNA methylation is essential to normal cell development. DNA methylation controls which genes produce proteins and which don’t.

DNA methylation patterns are established early in an embryo’s development, and remain stable in most locations in the body.

But in some places they change during cell differentiation — the process by which a stem cell becomes another type of cell.

A category of enzymes called DNA methyltransferases, or DNMTs, plays an important role in DNA methylation. The category includes the enzymes DNMT1, DNMT3A and DNMT3B.

Studies have suggested that DNMT3A and DNMT3B are crucial to nerve cell development and function.

A key piece of evidence is that mice with nervous system mutations of the DNMT3A gene not only have fewer nerve cells, but also movement problems. This suggests that the DNMT3A enzyme is important in the development and function of nerve and muscle cell communication — a process that is impaired in ALS.

“If you look at DNA methylation patterns in ALS patients, they are all over the place,” Dr. Evangelos Kiskinis, the lead author of the study, said in a press release. “Is it a driver of disease, or is it just a byproduct? Our study provides us with a platform to address these intriguing questions.”

Researchers used embryonic stem cells to try to learn more about DNA methylation’s role in movement nerve cell development. They differentiated the stem cells into movement nerve cells that lacked DNMT3A, DNMT3B or both.

One finding was that lack of DNMT3B affected DNA methylation patterns but had little effect on movement nerve cell development. In contrast, lack of DNMT3A impaired this  development by crimping the production of certain proteins.

“DNA methylation governs gene expression [protein production] potential and hence cell identity,” Kiskinis said. “As stem cells transition from early progenitors to committed progenitors to developed neurons [nerve cells], DNA methylation allows for the induction [triggering] or suppression of key transcription factors [proteins]. In turn, those transcription factors govern cell type function and specificity.”

Researchers also discovered that lack of DNMT3A led to a decrease in the branching of dendrites — nerve cell projections involved in cell-to-cell communication.

Collectively the findings suggested that DNMT3A plays a key role in the development and functioning of movement nerve cells.

In the future, Kiskinis wants to investigate the relationship between mutations of the DNMT3A gene and the development of ALS.