Deletion of a stem cell factor promotes TBI recovery in mice

November 20, 2017, UT Southwestern Medical Center
(l-r) Dr. Xiaoling Zhong and Dr. Chun-Li Zhang. Credit: UT Southwestern Medical Center

UT Southwestern molecular biologists today report the unexpected finding that selectively deleting a stem cell transcription factor in adult mice promotes recovery after traumatic brain injury (TBI).

The Centers for Disease Control and Prevention defines TBI as a bump, blow, or jolt to the head that disrupts normal brain function, ranging from mild - brief changes in mental status - to severe, marked by an extended period of unconsciousness or memory loss. In humans, most TBIs are mild and are called concussions.

"Our results reveal that SOX2-dependent signaling pathways in reactive astrocytes are targets for brain recovery after traumatic injury," said Dr. Chun-Li Zhang, Associate Professor of Molecular Biology and in the Hamon Center for Regenerative Science and Medicine. Dr. Zhang is co-corresponding author of the study published today in the journal Cerebral Cortex.

Star-shaped astrocytes are the most abundant subgroup of , which support and insulate neurons in the brain and spinal cord. The stem cell transcription factor SOX2, which is critical for , cell reprogramming, and brain development, also is activated in astrocytes in the adult brain. Its expression in these increases in response to TBI, the researchers said.

Some earlier studies had indicated that reactive astrocytes are necessary for recovery following brain or spinal cord injury despite astrocytes' association with the formation of glial scars.

In this study, the researchers found that conditional deletion of Sox2 - the gene encoding the SOX2 stem cell transcription factor - and the associated dampening of reactivity appear to promote functional recovery, including behavioral recovery, after , said Dr. Zhang, a W.W. Caruth, Jr. Scholar in Biomedical Research.

"Our finding runs counter to the belief that increasing the reactivity of astrocytes and other glial cells in the brain helps maintain tissue integrity following TBI. That's why the accelerated recovery from injury after deletion of the transcription factor in reactive astrocytes was unexpected," he said.

A better understanding of the molecular mechanisms controlling reactive astrocyte function is fundamental to therapeutic interventions for brain trauma. Because SOX2 functions in several signaling pathways, the study opens up new areas for investigation, Dr. Zhang said.

The mice in the study were engineered so that the Sox2 gene could be conditionally deleted during adulthood. All of the mice produced normal amounts of SOX2 during development, when the transcription factor plays a critical role in the genesis of embryonic and neural stem cells.

The scientists conditionally deleted the Sox2 gene in some , left the gene intact in others, and then compared the two groups under normal conditions and in response to TBI. Under normal conditions, the researchers detected no differences in astrocyte survival or animal behavior in the presence or absence of the Sox2 gene.

However, in response to TBI, the knockout mice showed greatly reduced astrocyte reactivity compared with controls. Unexpectedly, those mice recovered from injury significantly better than the controls - both physically and behaviorally - the scientists report. The knockout mice also did better on tests of behaviors associated with the brain's prefrontal cortex, the area that regulates complex thinking, emotions, and behavior in humans. Sox2 deletion had no significant effect on learning and memory associated with the 's hippocampus region, said Dr. Xiaoling Zhong, the co-lead author and a postdoctoral researcher in the laboratory.

"Our results reveal that SOX2 plays an important role in TBI-induced reactive astrocytes and behavioral deficits. We look forward to exploring how SOX2-dependent pathways could be targeted for recovery after TBI," Dr. Zhang said.

Explore further: Brain astrocytes linked to Alzheimer's disease

Related Stories

Brain astrocytes linked to Alzheimer's disease

November 20, 2017
Astrocytes, the supporting cells of the brain, could play a significant role in the pathogenesis of Alzheimer's disease (AD), according to a new study from the University of Eastern Finland. This is the first time researchers ...

Biomarkers can reveal traumatic brain injury, even when concussions don't show up on CAT scan

October 27, 2017
UCLA researchers have identified four biomarkers that could help doctors diagnose brain trauma and concussions through a simple blood test. The biomarkers are proteins, from brain cells called astrocytes, which are released ...

Scientists find interaction between two key proteins regulates development of neurons

September 14, 2017
Salk Institute scientists have discovered that an interaction between two key proteins helps regulate and maintain the cells that produce neurons. The work, published in Cell Stem Cell on September 14, 2017, offers insight ...

Researchers generate new neurons in brains, spinal cords of living adult mammals

February 25, 2014
UT Southwestern Medical Center researchers created new nerve cells in the brains and spinal cords of living mammals without the need for stem cell transplants to replenish lost cells.

CD38 gene is identified to be important in postnatal development of the cerebral cortex

April 7, 2017
The brain consists of neurons and glial cells. The developmental abnormality of glial cells causes various diseases and aberrant cerebral cortex development. CD38 gene knockout is shown to cause aberrant development of glial ...

Recommended for you

Separate brain systems cooperate during learning, study finds

February 21, 2018
A new study by Brown University researchers shows that two different brain systems work cooperatively as people learn.

How the brain tells our limbs apart

February 21, 2018
Legs and arms perform very different functions. Our legs are responsible primarily for repetitive locomotion, like walking and running. Our arms and hands, by contrast, must be able to execute many highly specialized jobs—picking ...

Cognitive benefits of 'young blood' linked to brain protein in mice

February 21, 2018
Loss of an enzyme that modifies gene activity to promote brain regeneration may be partly responsible for age-related cognitive decline, according to new research in laboratory mice by UC San Francisco scientists, who also ...

Therapeutic antibodies protected nerve–muscle connections in a mouse model of Lou Gehrig's disease

February 20, 2018
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, causes lethal respiratory paralysis within several years of diagnosis. There are no effective treatments to slow or halt this devastating disease. Mouse ...

Brain immune system is key to recovery from motor neuron degeneration

February 20, 2018
The selective demise of motor neurons is the hallmark of Lou Gehrig's disease, also known as amyotrophic lateral sclerosis (ALS). Yet neurologists have suspected there are other types of brain cells involved in the progression ...

Brain liquefaction after stroke is toxic to surviving brain: study

February 20, 2018
Scientists have known for years that the brain liquefies after a stroke. If cut off from blood and oxygen for a long enough period, a portion of the brain will die, slowly morphing from a hard, rubbery substance into liquid ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.