Researchers develop new animal model to study rare brain disease

March 17, 2017, Kanazawa University
Left: Cross-sectional view of the cerebrum in normal ferret. Neurons are localized in the cerebral cortex, the surface layer of the cerebrum. Since the surface of the cerebrum has folds (gyri), the layer containing neurons winds on its way. Right: Cross-sectional view of the cerebrum in TD ferret. Clusters of neurons (indicated by arrows) are found deep in the cerebrum, which are not detected in the cerebrum of normal ferret. They are called 'periventricular nodular heterotopia,' PNH. In addition, in the surface layer, a larger number of smaller folds (gyri) are seen than normal (indicated by asterisks). They are called polymicrogryri. Credit: Kanazawa University

Thanatophoric dysplasia (TD) is an intractable disease causing abnormalities of bones and the brain. In a recent study of ferrets, which have brains similar to those of humans, researchers using a newly developed technique discovered that neuronal translocation along radial glial fibers to the cerebral cortex during fetal brain development is aberrant, suggesting the cause underlying TD.

In TD cases, the limb and rib bones are shorter than normal, and manifest, including polymicrogyria and periventricular nodular heterotopia. Previous research has determined that a gene, fibroblast growth factor receptor 3 (FGFR3), is responsible. However, as a result of TD rarity and the difficulty of obtaining brain samples from human patients, the pathophysiology of TD is largely unknown, and effective therapy has not been established.

The present research team of Kanazawa University generated an of TD using ferrets that reproduces the brain found in human TD patients. By using this animal model, the team elucidated the formation process of polymicrogyria, one of the abnormalities found in the TD brain. The team has also investigated the formation process of PNH, the other brain abnormality found in human TD patients.

First, PNH was analyzed in terms of composing cell types to reveal that a large number of but few glial cell exist in PNH. In a healthy brain, neurons are found in the cerebral cortex near the brain surface. The researchers believe that during fetal brain development, PNH formation might be induced by the inability of neurons to translocate themselves to the . The researchers found that the spatial arrangement of radial glial cells was distorted; radial glial fibers are believed to serve as the "track" for neurons to translocate themselves. Thus, the distortion of radial glial fibers seems to be a reason for aberrant localization of neurons.

The green oval indicates a neuron while the orange oval with a protruding fiber, radial glia. Neurons are thought to translocate themselves to the cerebral cortex. Left: In the developing brain of normal ferret, neurons translocate themselves to the cerebral cortex along the radial glial fiber. Right: In the developing brain of TD ferret, some neurons cannot reach the cerebral cortex due to aberrant radial glial fibers, but stay deep in the cerebrum to form clusters of neurons, i.e., PNH. Credit: Kanazawa University

Research on abnormalities of bones in TD is progressing with iPS cells at Kyoto University, and it is expected that the whole aspect of TD with and bone abnormalities would be elucidated and that the therapeutic methods would be developed. The present study on PNH was only possible using the experimental technique for ferrets developed by the research team. This animal model technique could also contribute to studies of other neurological diseases that have been difficult to investigate with conventional model animals.

Explore further: Researchers discover a gene's key role in building the developing brain's scaffolding

More information: Naoyuki Matsumoto et al, Pathophysiological analyses of periventricular nodular heterotopia using gyrencephalic mammals, Human Molecular Genetics (2017). DOI: 10.1093/hmg/ddx038

Related Stories

Researchers discover a gene's key role in building the developing brain's scaffolding

July 2, 2013
(Medical Xpress)—Researchers have pinpointed the role of a gene known as Arl13b in guiding the formation and proper placement of neurons in the early stages of brain development. Mutations in the gene could help explain ...

Humans' big brains might be due in part to newly identified protein

November 12, 2014
A protein that may partly explain why human brains are larger than those of other animals has been identified by scientists from two stem-cell labs at UC San Francisco, in research published in the November 13, 2014 issue ...

Transplanted neurons incorporated into a stroke-injured rat brain

January 23, 2017
Today, a stroke usually leads to permanent disability – but in the future, the stroke-injured brain could be reparable by replacing dead cells with new, healthy neurons, using transplantation. Researchers at Lund University ...

Study implicates glial cells in fragile X syndrome

October 4, 2016
Research on fragile X syndrome, the most common inherited cause of mental retardation, has focused mostly on how the genetic defect alters the functioning of neurons in the brain. A new study focusing on a different type ...

Why neural stem cells may be vulnerable to Zika infection

March 30, 2016
Zika's hypothesized attraction to human neural stem cells may come from its ability to hijack a protein found on the surface of these cells, using it as an entryway to infection. In Cell Stem Cell on March 30, researchers ...

Glia, not neurons, are most affected by brain aging

January 10, 2017
The difference between an old brain and a young brain isn't so much the number of neurons but the presence and function of supporting cells called glia. In Cell Reports on January 10, researchers who examined postmortem brain ...

Recommended for you

Variants in non-coding DNA contribute to inherited autism risk

April 19, 2018
In recent years, researchers have firmly established that gene mutations appearing for the first time, called de novo mutations, contribute to approximately one-third of cases of autism spectrum disorder (ASD). In a new study, ...

Researchers discover link between gene variation and language

April 18, 2018
What shapes the basic features of a language?

Natural selection still at work in humans

April 18, 2018
Evolution has shaped the human race, with University of Queensland researchers finding signatures of natural selection in the genome that influence traits associated with fertility and heart function.

Gene therapy for beta-thalassemia safe, effective in people

April 18, 2018
In a powerful example of bench-to-bedside science showing how observations made in the lab can spark life-altering therapies in clinic, an international team of clinician-investigators has announced that gene therapy for ...

Potential lines of attack against prostate cancer

April 17, 2018
Researchers from The University of East Anglia (UEA) have contributed to the world's largest study into genes that drive prostate cancer – identifying 80 molecular weaknesses that could be targeted by drugs to treat the ...

Epstein-Barr virus linked to seven serious diseases

April 16, 2018
A far-reaching study conducted by scientists at Cincinnati Children's reports that the Epstein-Barr virus (EBV)—best known for causing mononucleosis—also increases the risks for some people of developing seven other major ...


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.