What causes autism? New research reveals a key factor in brain development

The results of this research reveal an important component in the underlying causes of congenital neural tube defects, intellectual disabilities, and autism risk.

Researchers from Texas A&M School of Medicine have provided answers to important questions regarding how the neocortex develops, providing new information about the root causes of intellectual disabilities.

A major advance in our understanding of how the brain develops has been made by researchers at Texas A&M University School of Medicine. This new research advances our understanding of how the region of the brain develops that distinguishes humans from other animals and sheds light on the causes of 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, an area of ​​the brain that governs higher order processes such as perception, cognition, and language. The surface area of ​​the neocortex reflects the high development of the mental capacity of the organism. For example, the neocortex of humans is only three times thicker than that of mice. However, the surface area of ​​the neocortex of humans is 1,000 times larger than that of mice. Autism spectrum disorders and intellectual impairment are among the developmental deficiencies caused by abnormalities in this region of the brain.

What is not known is how the 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 primary populations of neural stem cells, which serve as the building blocks of the brain, distribute themselves.

“There are many, what we will call, horizontally arranged individual processing units in the neocortex. The more surface area you have, the more surface area you have, said Vytas A. Bankaitis, Distinguished Professor in the School of Medicine, President of the EL Wehner-Welch Foundation in Chemistry, and co-author of this study. You can accommodate more of these processing units, published in cell reports. The question is, why is the surface area of ​​the neocortex so much larger in relation to its thickness as one climbs up the mammalian evolutionary tree? Why do neural stem cells spread themselves sideways because they multiply and do not pile on top of each other? “

This question is fundamental because when the cells do not spread, but instead accumulate, they create a thicker neocortex with a smaller surface area – a characteristic that has been observed in cases of intellectual disabilities and even autism.

“One of the most studied genetic causes of intellectual disability is a mutation in the gene that was originally called LIS1,” said Zhigang Xie, associate professor at the College of Medicine and co-author of the study. This genetic mutation will lead to a smooth brain, which is linked to intellectual disability. One typical observation is that the neocortex of the patient is thicker than normal. There are also very recent studies identifying common variations in the autistic brain that include abnormally thick regions of the neocortex in these 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 called interkinetic nuclear migration. They do this by utilizing a cytoskeleton network that acts like train tracks with actuators that move nuclei up or down in a closely organized manner. Although many ideas have been proposed, it remains a mystery why 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 study, Xie and Bankaitis provide answers to these questions.

As for reasoning, Bankaitis shows that when there are too many closely spaced cells in the embryonic stage of neocortical development, the up-and-down movement of their nuclei results in opposing the upward and downward forces that propagate the dividing neural stem cells.

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

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

“I think for the first time, this really brings together the molecules and signaling pathways that indicate how this process is controlled and why it is linked or linked to neurodevelopmental deficiency,” Bankais said. “We’ve taken a biochemical pathway, linked it to a cell’s biological pathway, and linked it to a signaling pathway that speaks to the nucleus to promote nuclear behavior that generates a complex brain-generating force. Now it’s full circle.”

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

“While there may be many reasons why the neocortex is thickening rather than spreading, our work offers a new perspective on why patients with autism and intellectual disabilities often display a thicker cerebral cortex,” Shih said. “The fact that the LIS1 gene product is an essential regulator of nuclear migration, including interkinetic nuclear migration that we study in this work, supports our conclusions in this paper.”

Reference: “Planar cell polarity axis/Phosphatidylinositol transporter protein regulates neocortical formation by supporting interkinetic nuclear migration” By Zhigang Xie and Vytas A. Bankaitis, May 31, 2022, Available here. Cell reports.
DOI: 10.1016 / j.celrep.2022.110869

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

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