Researchers from Texas A&M College of Medicine have provided answers to important questions about neocortical development, providing new insights into the root causes of intellectual disabilities.
A significant advance in our understanding of brain development has been made 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 the causes of 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 surface of the neocortex reflects the degree of development of mental abilities of an organism. For example, the human neocortex is only about three times thicker than that of the mouse. However, the human neocortex has a surface area 1,000 times larger than that of mice. Autism spectrum disorders and intellectual disabilities are among the developmental disabilities caused by malformations in this region of the brain.
What is unknown is how the evolutionary expansion of this section of the brain occurs selectively in favor of growing the surface of the neocortex 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 building blocks of the brain, distribute.
“There are many, what we’ll call, individual processing units that are arranged horizontally in the neocortex. The more surface area you have, the more you can accommodate these processing units,” said Vytas A. Bankaitis, professor emeritus at the College of Medicine, holder of the EL 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 so much larger relative to its thickness as one moves up the mammalian evolutionary tree? Why do neural stem cells spread in a lateral direction as that they proliferate and don’t they pile up on top of each other?
This question is key because when cells don’t spread out, but pile up, it creates 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 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 result in 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 that identify common differences in the autism brain, including abnormally thickened regions of the neocortex in these individuals.
Scientists have known for some time that when neural stem cells divide, their nuclei move up and down in their anatomical space based on the cell cycle, a process called interkinetic nuclear migration. They do this by using a cytoskeletal network that acts like train tracks with motors that move nuclei up or down in a tightly regulated way. Although several ideas have been proposed, it remains an enigma why nuclei move in this way, how this network of pathways 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 to 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 propagate dividing neural stem cells.
“Think of a tube of toothpaste,” Bankaitis said. “If you were to take this tube of toothpaste, put it in your hands, push from the bottom and push from the top, what would happen? It would flatten and spread out. That’s basically how it works. You have an upward force and a downward force caused by the movement of the nuclei which propagate these cells.
Xie and Bankaitis also demonstrate how the cells do this by linking together several distinct pathways that cooperate to “tell” 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 or associated with neurodevelopmental impairments,” Bankaitis said. “We took a biochemical pathway, linked it to a cellular biological pathway, and linked it to a signaling pathway that talks to the nucleus to promote nuclear behavior that generates force that develops a complicated brain. It is now a complete circuit.
The results of this study reveal an important factor in the underlying causes of autism risk, intellectual disabilities and birth defects of the neural tube. The new insights into the basic principles regulating the shape of the neocortex will also help to design in vitro brain culture systems that more accurately reflect the developmental processes of interest and improve the prospects for neurological drug development.
“While it may turn out that there are many reasons why a neocortex thickens rather than spreads, our work offers new insight into why patients with autism and impairments intellectuals often display a thicker cortex,” Xie said. “The fact that the LIS1 gene product is a central regulator of nuclear migration, including the interkinetic nuclear migration we study in this work, supports the conclusions we reach in this article.”
Reference: “Planar cell/phosphatidylinositol transfer protein polarity axis regulates neocortical morphogenesis by supporting interkinetic nuclear migration” by Zhigang Xie and Vytas A. Bankaitis, May 31, 2022, Cell reports.
The study was funded by the NIH/National Institutes of Health and the Robert A Welch Foundation.