The nervous system developing in a mouse embryo from head/anterior (red) to tail/posterior (cyan). - Kenzo Ivanovitch
For decades, biology textbooks have taught that developing nerve cells initially form the brain and over time, some transform into spinal cord, but a new study from researchers at the Francis Crick Institute challenges this view.
By investigating the development of central nervous system cells, engineered from embryonic stem cells, researchers have discovered that a critical decision is made earlier in cells than previously anticipated and this predetermines whether they form the brain or spinal cord.
This insight sheds light on the origin of different regions of the nervous system in embryos, and could help scientists to develop regenerative approaches for spinal cord injury and disease. The paper is published in Cell.
Running from head to tail in animals and humans, the central nervous system is divided into the brain, which contains the nerve cells responsible for complex information processing and decision making, and the spinal cord, containing nerve cells for sensing and moving the body. How the cells that make the two parts of the nervous system are formed in an embryo has been a long-standing question in developmental biology.
“Our work demonstrates that the formation of the spinal cord is predetermined in cells before they become neural cells,” says James Briscoe, senior author of the paper and head of the Crick’s Developmental Dynamics lab. “This challenges the textbook view of how the nervous system is formed, which suggested that neural cells progressively transition from brain to spinal cord.”
Biologists and computer scientists in collaboration
By combining cutting-edge developmental biology and embryonic stem cell techniques with computational genomics, the team were able to determine when cells became neural and adopted brain or spinal cord characteristics. This revealed a critical time window during development before formation of the nervous system, when cells acquire the ability to make spinal cord. Testing their findings in embryos, the team found that this critical window corresponds to between days 7 and 7.5 of mouse development.
The researchers took advantage of state-of-the-art genome sequencing technologies to generate novel molecular understanding of neural induction, the process of nervous system development. They found that by performing ATAC-seq – a technique that allows the discovery of active regions of DNA in the genome – they could distinguish neural cell types that make up different regions of the central nervous system.
“By tracking the chromatin accessibility landscape of neural cells over time, we could identify the transcription factors responsible for spinal cord fate and the context in which they operate,” says Sebastian Steinhauser, co-first author of the study and a Winton PhD student at the Crick.
“The interdisciplinary approach made possible by the facilities at the Crick provided us with a powerful way to resolve, on a genomic scale, how cells make decisions during development”, said Nicholas Luscombe, a senior Winton group leader and co-author of the study, who runs the Bioinformatics and Computational Biology Laboratory.
What’s behind the early cell-type decision?
The work revealed that during early development, the activity of a set of proteins, known as CDX transcription factors, establishes which cells can form spinal cord by altering the organisation of the genome in cells.
“These proteins not only appear to activate genes needed for the development of spinal neurons but also repress genes specific for brain neurons,” says Vicki Metzis, co-first author of the study and postdoc at the Crick.
She added: “Beyond our new understanding of how the nervous system forms, this study helps explain how to use embryonic stem cells to generate spinal cord neurons. Our findings suggest that trying to engineer spinal cord cells depends on timing. Knowing this critical time window exists will be beneficial for regenerative medicine.”