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What Causes Autism? New Research Uncovers a Key Factor in Brain Development

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The findings of this research reveal a significant component in the underlying causes of neural tube birth defects, intellectual disabilities, and autism risk.

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

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

For many years, scientists have recognized a significant relationship between mammalian intelligence and a thin layer of cells in the neocortex, the region of the brain that governs higher-order processes like cognition, perception, and language. The neocortex’s surface area reflects how highly developed an organism’s mental ability is. For instance, the human neocortex is only around three times thicker than the mouse equivalent. However, the human neocortex has a 1,000-fold larger surface area than that of mice. Autism spectrum disorders and intellectual impairments are among the developmental deficiencies caused by malformations in this region of the brain.

What is unknown is how evolutionary expansion of this section of the brain happens selectively in favor of growing the neocortex’s surface area at the cost of increasing its thickness. An important aspect of this process is how the initial populations of neural stem cells, which serve as the brain’s building blocks, distribute themselves.

“There are many, what we’ll call, individual processing units that are horizontally arranged in the neocortex. The more surface area you have, the more of these processing units you can accommodate,” said Vytas A. Bankaitis, Distinguished Professor at the College of Medicine, E.L. Wehner-Welch Foundation Chair in Chemistry, and co-author of this study, which was published in Cell Reports. “The question is, why is the neocortical surface area so much greater relative to its thickness as one climbs up the mammalian evolutionary tree? Why do neural stem cells spread themselves in a lateral direction as they proliferate and not pile on top of each other?”

This question is key because when the cells do not spread out, but instead pile up, it creates a thicker neocortex with a smaller surface area — a characteristic that has been observed in cases of intellectual disability and even autism.

“One of the most studied genetic causes of intellectual disability is a mutation in a gene that was originally called LIS1,” said Zhigang Xie, assistant professor at the College of Medicine and co-author of the study. “This genetic mutation will cause a smooth brain, which is associated with intellectual disability. And one typical observation is that the neocortex of the patient is thicker than normal. There are also very recent studies that identify common differences in the brain of autism that include abnormally thickened regions of the neocortex in those 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 so by employing a cytoskeletal network that acts like train tracks with engines that move the nuclei up or down in a closely regulated manner. Although several ideas have been proposed, it remains an enigma why the nuclei move in this way, how this network of train tracks is controlled, and what role interkinetic nuclear migration plays in development of the neocortex.

In their study, Xie and Bankaitis provide answers to these questions.

As for why, Bankaitis explains that when there are so many cells 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 spreads the dividing neural stem cells out.

“Think about a tube of toothpaste,” Bankaitis said. “If you were to take that toothpaste tube, put it between your hands, push up from the bottom and push down from the top, 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 spreads these cells out.”

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

“I think for the first time, this really puts together molecules and signaling pathways that indicate how this process is controlled and why it would be linked or associated with neurodevelopmental deficiencies,” Bankaitis said. “We have 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 uncover an important factor in the underlying causes of autism risk, intellectual disabilities and neural tube birth defects. The new knowledge on the basic principles regulating the shape of the neocortex will also help the design of in vitro brain culture systems that more accurately reflect the developmental processes of interest and improve the prospects for neurological drug development.

“While there might prove to be many reasons why a neocortex thickens instead of spreads, our work provides a new perspective on why patients with autism and intellectual disabilities often display a thicker cortex,” Xie said. “The fact that the LIS1 gene product is a core regulator of nuclear migration, including the interkinetic nuclear migration that we study in this work, supports the conclusions we reach 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, 31 May 2022, Cell Reports.
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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