Brain Signals Rotating Test

What Causes Autism? New research reveals a key factor in brain development

Brain Signals Rotating Test

The findings of this study reveal an important component in the underlying causes of neural tube birth defects, intellectual disabilities and autism.

Researchers at the Texas A&M College of Medicine have provided answers to important questions about how the neocortex develops by providing new information about the root causes of intellectual disability.

Significant advances in our understanding of how the brain develops has been achieved by researchers at Texas A&M University College of Medicine. This new research advances our understanding of how the area of ​​the brain that distinguishes humans from other animals develops and sheds light on the causes of intellectual disabilities, such as autism spectrum disorders.

For many years, scientists have recognized a significant link between mammalian intelligence and a thin layer of cells in the neocortex, the region of the brain that controls higher-order processes such as cognition, perception and language. The surface of the neocortex reflects how highly developed an organism’s mental capacity is. For example, the human neocortex is only about three times thicker than the mouse equivalent. However, the human neocortex has a surface area 1000 times larger than that of mice. Autism spectrum disorders and intellectual disorders are among the developmental disorders caused by malformations in this part of the brain.

What is unknown is how evolutionary expansion of this part of the brain occurs selectively in favor of growing the surface of the neocortex at the expense of increasing its thickness. An important aspect of this process is how the initial populations of neural stem cells, which serve as the building blocks of the brain, are distributed.

“There are many, what we will call, individual processing units arranged horizontally in the neocortex. The more surface area you have, the more of these processing units you can accommodate,” said Vytas A. Bankaitis, Distinguished Professor in the College of Medicine, EL Wehner-Welch Foundation Chair in Chemistry, and co-author of this published study. in Mobile Reports. “The question is, why is the neocortical surface so much larger in proportion to its thickness when climbing the mammalian evolutionary tree? Why do neural stem cells spread in a lateral direction as they multiply and don’t stack on top of each other?”

This question is critical because when the cells don’t spread out, but pile up, they create a thicker neocortex with a smaller surface area — a feature that has been observed in cases of intellectual disability and even autism.

“One of the most widely studied genetic causes of intellectual disability is a mutation in a gene originally called LIS1,” said Zhigang Xie, an assistant professor in the College of Medicine and co-author of the study. “This genetic mutation produces a smooth brain, which is associated with intellectual disability. And a typical observation is that the patient’s neocortex is thicker than normal. There are also very recent studies identifying common differences in the brain of autism, including abnormally thickened areas of the neocortex in those individuals.

Scientists have known for some time that when neural stem cells divide, their nuclei move up and down their anatomical space as a function of the cell cycle, a process called interkinetic nuclear migration. They do this by using a cytoskeleton network that acts like train tracks with motors that move the nuclei up or down in a tightly controlled manner. While several ideas have been suggested, it remains a mystery why the nuclei move in this way, how this network of train tracks is controlled, and what role interkinetic nuclear migration plays in the development of the neocortex.

In their research, Xie and Bankaitis answer these questions.

As for why, Bankaitis explains that when so many cells are so close together in the embryonic stage of neocortical development, the movement of their nuclei up and down causes opposing upward and downward forces that spread the dividing neural stem cells.

“Think of a tube of toothpaste,” Bankaitis said. “If you were to take that tube of toothpaste, put it between your hands, push it from bottom to top and top to bottom, what would happen? It would flatten and spread out. That’s essentially how this works. You have an upward force and a downward force caused by the movement of the nuclei that spread these cells.

Xie and Bankaitis also show how the cells do this by connecting several different pathways that work together to “tell” the newborn neural stem cells where to go.

“I think for the first time this really brings together molecules and signaling pathways that indicate how this process is controlled and why it would be linked to or associated with neurodevelopmental deficits,” Bankaitis said. “We’ve taken a biochemical pathway, linked it to a cell biological pathway and linked it to a signaling pathway that talks to the nucleus to promote the nuclear behavior that generates a force that develops a complicated brain. It’s now a complete circuit.”

The results of this study reveal an important factor in the underlying causes of autism, intellectual disabilities and neural tube birth defects. The new knowledge about the basic principles governing the shape of the neocortex will also help design in vitro brain culture systems that more accurately reflect the developmental processes of interest and improve the prospects for neurological drug development.

“While there may turn out to be many reasons why a neocortex gets thicker instead of expanding, our work offers a new perspective on why patients with autism and intellectual disabilities often show a thicker cortex,” Xie said. “The fact that the LIS1 gene product is a nuclear regulator of nuclear migration, including the interkinetic nuclear migration we study in this work, supports the conclusions we draw in this paper.”

Reference: “Phosphatidylinositol transfer protein/planar cell polarity axis regulates neocortical morphogenesis by supporting interkinetic nuclear migration” by Zhigang Xie and Vytas A. Bankaitis, May 31, 2022, Cell reports.
DOI: 10.116/j.celrep.2022.110869

The study was funded by the NIH/National Institutes of Health and the Robert A Welch Foundation.

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