Discover the key factor in the development of the neocortex

Summary: A new study sheds light on how the neocortex develops in the human brain.

source: Texas A&M

Scientists at Texas A&M University School of Medicine have made a startling discovery about brain evolution.

This new information contributes to our understanding of how the part of the brain that makes humans smarter than other mammals evolved, and provides insights into the causes of intellectual disabilities, including autism spectrum disorders.

For years, experts have known that a thin layer of cells in the neocortex – the part of the brain that controls higher-order functions such as cognition, cognition and language – is directly linked to intelligence in mammals.

The greater the surface area of ​​the neocortex, the greater the mental capacity of this organism to develop. For example, the thickness of the neocortex of humans is three times that of mice.

However, the surface area of ​​the human neocortex is a thousand times larger than that of mice. Abnormalities in this part of the brain develop into developmental deficits that include autism spectrum disorders and intellectual disabilities.

What is not understood is how the evolutionary expansion of this part of the brain occurs preferentially in favor of expanding the surface area of ​​the neocortex at the expense of increasing its thickness. How the first groups of neural stem cells – the building blocks of the brain – distribute themselves is a key factor in this process.

“There are many, what we 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, Chair 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 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 sideways as they proliferate and not stack on top of each other?”

This question is fundamental because when 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 in 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 through the use of a network of the cytoskeleton 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 neocortical development.

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 connecting several distinct pathways that work together to “tell” nascent neural stem cells where to go.

This shows a schematic diagram of the study
The greater the surface area of ​​the neocortex, the greater the mental capacity of this organism to develop. credit: researchers

“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’s being linked or linked to neurodevelopmental deficiency,” Bankites 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. It’s now 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 aid in the design of in vitro brain culture systems that more accurately reflect developmental processes of interest and improve prospects for neuropharmaceutical development.

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“While there may be many reasons for the neocortex to thicken rather than spread, 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.”

About this genetics and neurodevelopmental news

author: Lindsey Hendricks
source: Texas A&M
Contact: Lindsey Hendricks – Texas A&M
picture: The image is attributed to the researchers

original search: open access.
The Phosphatidylinositol/planar cell polarity axis transport protein regulates neocortical formation by supporting interkinetochore nuclear migration.Written by Zhigang Xie et al. cell reports


The Phosphatidylinositol/planar cell polarity axis transport protein regulates neocortical formation by supporting interkinetochore nuclear migration.


  • PITPNA/PITPNB supports membrane trafficking for a subset of ncPCP receptors
  • PITP/ncPCP stimulates actomyosin activity in neural stem cells in the embryonic neocortex
  • PITP/ncPCP-dependent actomyosin activity enhances interkinetic nuclear migration
  • Interkinetic nuclear migration enhances lateral versus radial expansion of the neocortex


The neocortex expands explosively during embryonic development. Early clusters of neural stem cells (NSCs) form a thin stratified pseudo-epithelium whose circumference defines the circumference of the adult neocortex.

The new cortical complexity is accompanied by a disproportionate expansion of the NSC layer in its tangent dimension to increase the tissue surface area. How this disproportionate expansion is controlled is still unknown.

We show that the phosphatidylinositol transfer protein (PITP)/planar cell Wnt signaling axis (ncPCP) promotes the tangential expansion of neocortical development.

PITP signaling supports trafficking of specific ncPCP receptors from the NSC Golgi system to stimulate actomyosin activity important for cell cycle-dependent kinetic nuclear migration (IKNM). In turn, IKNM enhances the lateral dispersal of newborn NSCs and the transverse growth of the cerebral wall.

These results clarify the functional roles of IKNM in NSC biology and identify tissue malformation resulting from IKNM impairment as a risk factor for autism, brain developmental disabilities and neural tube birth defects.