Why do motor neurons form faster?

Motor neurons, the nerve cells of the spinal cord that control muscle movement, form much faster than other neurons during development of the vertebrate spinal cord. Reconstruction of how the activity of genes changes as motor neurons form revealed that this effect is due to the activity of the Olig2 gene product, which promotes motor neuron formation by directly interfering with the expression of Hes genes - known antagonists of neuron formation.

HFSP Long-Term Fellow Andreas Sagner and colleagues
authored on Mon, 19 February 2018

How the right types of cells are produced at the right time and right number in embryos has fascinated developmental biologists for decades. A new study from scientists at the Francis Crick Institute and UCLA sheds light on this question by studying the molecular mechanisms that regulate the number and speed by which motor neurons form in the embryo.

This discovery closes a long-standing gap in our understanding by demonstrating why motor neurons form much faster in the spinal cord than other types of neurons. The work also has important implications for producing motor neurons from embryonic stem cells in the lab, that can be used to study conditions such as amyotrophic lateral sclerosis (also known as Lou Gehrig’s disease) and spinal muscular atrophy.

Figure: Embryonic stem cells differentiating into neural progenitors (blue) and motor neurons (red and green).

During embryonic development of the spinal cord, different types of nerve cells are formed from precursors, so called neural progenitors. It has been known for a long time that different types of neurons form at differing speeds during development, with motor neurons forming faster than the other types of nerve cells that populate the spinal cord. To understand why this is, the team used the latest molecular techniques to assess how the activity of genes change as neurons form. This was achieved using an approach called single cell transcriptional profiling that allows the activity of all genes in individual cells to be measured simultaneously. This gave the team snapshots of global gene activity in about 200 cells that were in the process of becoming motor neurons. To analyse these data the team developed custom computer software to reconstruct how gene activity changes as motor neurons form.

The analysis suggested that the product of a gene called Olig2, which is only expressed in the precursors of motor neurons, promotes the formation of these neurons by interfering with the activity of several members of another gene family - the Hes genes. These are known to antagonize the development of neurons. The team then went on to confirm these predictions with experiments in the spinal cord of developing embryos as well as using motor neurons generated from embryonic stem cells.

Dr Andreas Sagner from the Francis Crick Institute, first author of the study and recipient of a postdoctoral HFSP Long-Term Fellowship, said “The molecular mechanism we uncovered helps us to better understand how gene interactions govern the development of the spinal cord. It also holds promise for disease modelling and regenerative medicine as motor neurons are a clinically relevant cell type. The global reconstruction of the changes in gene activity provides previously unavailable information about the genetic processes governing motor neuron development. Our results will likely serve as an important reference point for future studies that focus on modelling degenerative diseases in motor neurons.” 


Olig2 and Hes regulatory dynamics during motor neuron differentiation revealed by single cell transcriptomics. Sagner, A.*, Gaber, Z.*, Delile, J.*, Kong, J.H., Rousso, D.L., Pearson, C.A., Weicksel, S.E., Mousavy Gharavy, S.N., Briscoe, J., Novitch, B.G., PLOS Biol. Public Library of Science; 2018;16: e2003127. Available: https://doi.org/10.1371/journal.pbio.2003127.

Pubmed link