The exact causes of schizophrenia are unknown, but past research has suggested that some individuals with the condition possess certain genetic variations. Now, researchers at Johns Hopkins University School of Medicine in Baltimore, MD, say they have begun to understand how one schizophrenia-related genetic variation influences brain cell development.

The research team, led by Dr. Guo-li Ming, a professor of neurology and neuroscience at the Institute for Cell Engineering at Johns Hopkins, recently published their findings in the journal Cell Stem Cell.

Schizophrenia is a disabling brain disorder that affects around 24 million people worldwide. The condition can cause hallucinations, delusions, dysfunctional thoughts and repetitive and agitated body movements.

According to the researchers, previous studies have found that people with schizophrenia have a missing piece in an area of the genome known as 15q11.2.

To find out how this missing piece affects the developing brain, the team analyzed skin cells from schizophrenia patients who were missing a part of 15q11.2 on one of their chromosomes. Since each individual has two copies of their genome, each subject also possessed one complete copy of 15q11.2.

These skin cells were then grown in a dish and enticed to become induced pluripotent stem cells (iPSCs) before becoming neural progenitor cells - stem cells that reside in the developing brain.

Lower CYFIP1 protein production 'triggers abnormalities in brain cell development'

The researchers explain that when human neural progenitor cells are grown in a dish, they usually form an organized ring pattern. But they found that the cells that were missing a part of 15q11.2 did not.

The team then set out to determine which of four genes in the missing piece of the 15q11.2 genome caused the neural progenitor cells to form in an abnormal fashion.

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The picture on the left shows the usual ring pattern of neural progenitor cell growth in a dish (highlighted by the red circle), while the picture on the right shows growth when a part of the 15q11.2 genome is missing.
Image credit: Ki-Jun Yoon/Johns Hopkins Medicine.

Through engineering neural progenitor cells to produce lower levels of protein than normal, they found that a gene called CYFIP1 caused abnormal ring formation.

To investigate further, the researchers modified the genomes of neural progenitor cells in the embryos of mice so they would produce less of the protein created by the CYFIP1 gene.

The team found that the brain cells of fetal mice displayed similar abnormalities to those found in the human neural progenitor cells grown in a dish. The researchers say this is because the CYFIP1 gene helps build the structure of each cell, so loss of the protein it produces impairs the cells' adherens junctions - areas where the structure of each cell meets another.

Furthermore, the researchers found that a reduction in CYFIP1 protein caused some brain cells in the fetal mice to reach the incorrect layer of the brain.

"During development, new neurons get in place by 'climbing' the tendrils of neural progenitor cells," explains Dr. Ming. "We think that disrupted adherens junctions don't provide a stable enough anchor for neural progenitors, so the 'rope' they form doesn't quite get new neurons to the right place."

Combination of WAVE variation and deletion in CYFIP1 'increases schizophrenia risk'

In addition, the team discovered that the CYFIP1 gene plays a role in a group of proteins called WAVE, which are crucial to the structural development of cells. However, they note that many people with a deletion in the CYFIP1 gene do not develop schizophrenia, which led them to suspect a second abnormality was at play.

From analyzing data of genome-wide association research, the team discovered that a combination of a variation in a WAVE signaling gene - called ACTR2/Arp2 - and a deletion in the CYFIP1 gene significantly increased the risk of schizophrenia, compared with changes in ACTR2/Arp2 and a deletion in the CYFIP1 gene alone.

Commenting on the team's findings, Dr. Ming says:

"This is an important step toward understanding what physically happens in the developing brain that puts people at risk of schizophrenia."

As well as increasing the understanding of how schizophrenia develops, the researchers say the technique used in their study could be used to better the understanding of other mental health disorders.

"Using induced pluripotent stem cells from people with schizophrenia allowed us to see how their genes affected brain development," says study co-author Prof. Hongjun Song, also a professor of neurology and neuroscience at Johns Hopkins. "Next, we'd like to investigate what effects remain in the mature brain."

Medical News Today recently reported on a study published in the journal Neuron, in which researchers found that a gene called SETD1A may play a significant role in the development of schizophrenia.