What is the cause of autism? New research uncovers a key factor in brain development

brain signal rotating test

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

Researchers at Texas A&M College of Medicine have provided answers to important questions related to how the neocortex develops, providing new insight into the root causes of intellectual disabilities.

Researchers have made a significant advance in our understanding of how the brain develops Texas A&M University College of Medicine, This new research advances our understanding of how the area of ​​the brain that differentiates humans from other animals develops and causes intellectual disabilities, such as autism spectrum disorders.

For many years, scientists have recognized an important connection 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 area of ​​the neocortex reflects how developed an organism’s mental capacity is. For example, the human neocortex is about three times thicker than its mouse counterpart. However, the surface area of ​​the human neocortex is 1,000 times larger than that of mice. Autism spectrum disorder and intellectual impairment are among the developmental deficits caused by malformations in this area of ​​the brain.

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

“There are many, we call, individual processing units that are arranged horizontally in the neocortex. The more surface area you have, the more of these processing units you can accommodate,” says Vyas A. Bankitis, Distinguished Professor in the College of Medicine, E.L. Weiner-Welch Foundation Chair in Chemistry, and co-author of this study, which was published in cell report, “The question is, why is the neocortical surface area so high relative to its thickness as one climbs the mammalian evolutionary tree? Why do neural stem cells spread themselves in a lateral direction as they grow and do not stack on top of each other?

This question is important because when cells do not proliferate, but instead stack, it forms a thicker neocortex with a smaller surface area – a feature seen in cases of intellectual disability and even autism. Has been.

“One of the most studied genetic causes of intellectual disability is a mutation in a gene that was originally called LIS1,” said study co-author Xigang Xie, an assistant professor in the College of Medicine and co-author of the study. “This genetic mutation will lead to 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 showing normal differences in the brain of autism. identify those involving abnormally thickened areas of the neocortex in individuals.”

Scientists have known for some time that as neural stem cells divide, their nuclei move up and down within their anatomical space as a function of the cell cycle, a process known as interkinetic nuclear migration. They do this by employing a cytoskeletal network that acts like train tracks with engines that move nuclei up or down in a closely regulated manner. Although many ideas have been proposed, it remains a mystery why nuclei move 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 study, Xie and Bankaitis provide answers to these questions.

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

“Think of a tube of toothpaste,” Bankitis said. “If you put that tube of toothpaste between your hands, push from the bottom up and push down from the top, what will happen? It will flatten and spread out. It basically works like this. You have an upward and downward force because of the motion of the nuclei propelling these cells.”

Xie and Bankaitis also demonstrate how cells do this by linking together several different pathways that cooperate to “tell” nascent neural stem cells where to go.

“I think for the first time, it really puts together molecules and signaling pathways that indicate how this process is regulated and why it would or would be linked to neurodevelopmental deficiencies,” Bankitis 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 nuclear behavior that generates a complex brain-evolving power.” . It’s a complete circuit now.”

The results of this study highlight an important factor in the risk of autism, the underlying causes of intellectual disabilities and neural tube birth defects. New knowledge on the basic principles regulating the shape of the neocortex will also aid in the design of in vitro brain culture systems that more accurately reflect the developmental processes of interest and improve prospects for neurologic drug development.

“While there may be many proven reasons why a neocortex is thicker rather than diffuse, our work provides a new perspective on why patients with autism and intellectual disability often display a thicker cortex,” Xie said. . “The fact that the LIS1 gene product is a key regulator of nuclear migration, including the interkinetic nuclear migration we study in this work, supports the findings in this paper.”

Reference: “Phosphatidylinositol transfer protein/planar cell polarity axis regulates neocortical morphogenesis by supporting interkinetic nuclear migration” by Zhigang Xie and Waitas A. Bankitis 31 May 2022. cell report.
DOI: 10.1016/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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