A little pressure helps shape the precursors of the brain


In the human embryo, the neural tube is formed between the 22nd and 26th day of pregnancy. Later, the brain and spinal cord will develop from this tube. The neural tube forms when an elongated flat tissue structure, the neural plate, bends lengthwise in a U-shape and closes to form a tube. What is driving this development is not yet clear. Researchers from the group of Dagmar Iber, Professor of Computational Biology in the Department of Biosystems Science and Engineering at ETH Zurich in Basel, have now been able to show that the surrounding tissue is likely to play an important role in exerting the outside.

The formation of the neural tube is an extremely important step in embryonic development, as Professor Iber from ETH points out. In about one in a thousand embryos, this tube does not form completely. These children are born with a malformation of the spine called spina bifida (from the Latin for “split spine”); in extreme cases, they are born with an “open back” (spina bifida aperta) which requires surgery. To better prevent this type of birth defect, scientists would like to understand neurulation – the process of neural tube formation – in as much detail as possible.

“Over the past few decades, this question has been the subject of intense research,” says Roman Vetter, scientist in Iber’s group and co-author of the new study, which the researchers are now publishing in the journal PNAS. The linear regions in the middle and at the sides of the neural plate are known to be particularly strongly curved. These regions are called hinge points. Until now, scientists assumed that local biochemical signals in the cells of the neural plate lead to the formation of these hinge points, and that the hinge points play an active role in the formation of the neural tube. However, there has been no explanation as to why the articulation points form exactly where they form.

Computer modeling leads the way

The ETH researchers are now postulating an alternative mechanism, whereby the neural plate does not actively bend, driven by the points of articulation, to form a tube. On the contrary, the neural plate initially adopts a slightly curved shape for anatomical reasons. Subsequently, the tissue located on either side of the neural plate (ectoderm and mesoderm) expands. This applies lateral pressure to the neural plate and causes it to passively form a tube.

The researchers arrived at these results using computer modelling. Using existing image data from human and mouse embryos, the researchers created a computer model of neurulation based on the physical laws of nature. They then used a supercomputer at ETH Zurich to simulate several possible mechanisms of neural tube formation.

This showed that the processes were best explained by the expansion of surrounding tissues. “We use this to demonstrate that tipping points can occur as a result of external pressure. So they are probably not drivers of neurulation, as previously thought, but a side effect of it,” says Iber. Instead, the conductor appears to be the surrounding tissue.

Additional mechanism in the lower back

Especially in the upper back, neurulation can be explained by the expansion of the adjacent tissue, because for anatomical reasons the neural plate is already slightly pre-bent. Further down the future back, this initial curvature is absent; the neural plate is flat in this area.

Thanks to their modeling, the ETH scientists were able to show that here, too, neurulation can be explained by external forces: protein fibers and anchoring proteins help pull the neural plate together like a zipper. This causes the neural plate to curve and close into a tube.

According to the researchers, the fact that the mechanisms differ in the upper and lower back could explain why spinal malformations do not occur with the same frequency throughout the back. Spina bifida is most common in the lower back, where the surrounding tissues are less supportive.

“We were able to show that mechanical effects are responsible for neurulation,” says Vetter, “and our computational modeling was key to revealing this in the first place.” Professor Iber from ETH adds: “It is impossible to demonstrate and understand a mechanical effect using only biological and genetic experiments, without such simulations. Experimental researchers are now likely to try to confirm the ETH researchers’ predictions with animal experiments.

The objective is also to get a little closer to the causes of defects and therefore their prevention. Folic acid deficiency and other deficiency symptoms are known to promote these spinal malformations. Further research is needed to fully understand the underlying mechanisms.

Reference: de Goederen V, Vetter R, McDole K, Iber D. Emergence of the hinge point in mammalian spinal neurulation. Proceedings of the National Academy of Sciences. 2022;119(20):e2117075119. do I:10.1073/pnas.2117075119

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