Researchers from the Francis Crick Institute and UCLA, USA, have uncovered the inner workings of a gene network that regulates the development of spinal motor neurons in the growing embryo. The research answers a long-standing question about why motor neurons - the nerve cells of the spinal cord that control muscle movement - form much faster than other types of neurons.
The study from the labs of James Briscoe at the Crick and Bennett Novitch at UCLA is published in the journal PLOS Biology and has important implications for facilitating the production of motor neurons from stem cells in the lab. Stem cell-derived motor neurons could be used to repair the diseased or damaged spinal cord and to study neurodegenerative diseases such as amyotrophic lateral sclerosis - also known as motor neuron disease - and spinal muscular atrophy.
"This study provides an unprecedented detailed view of how embryos produce the different cell types found in the spinal cord," says Bennett. "The new experimental techniques we used, combined with collaborative efforts of biologists and computer scientists, are allowing us to gain new insight into the exquisite accuracy of embryonic development."
During embryonic development of the spinal cord, different types of nerve cells are formed from precursor cells, 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. However, why and how motor neurons develop in this way was not understood.
The research 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, which 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 analyze these data, the team developed custom computer software to reconstruct how gene activity changes as motor neurons form.
The analysis suggested that a protein produced by a gene called Olig2, which is only expressed in the neural progenitors that create motor neurons, promotes motor neuron formation by interfering with the activity of several members of another gene family, the Hes genes. The Hes genes are known to prevent the development of neurons. The researchers confirmed Olig2's role in promoting motor neuron formation by increasing or blocking the function of Olig2 in the spinal cords of developing mouse and chicken embryos, as well as during motor neuron formation in mouse embryonic stem cells.
Crick postdoc and first author of the study, Andreas Sagner, says: "The molecular mechanism we uncovered helps us 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."