Nav: Home

Abnormal development of the brain in an intractable disease, thanatophoric dysplasia

March 17, 2017


Thanatophoric dysplasia (TD) is an intractable disease designated by Ministry of Welfare, Health and Labor (MWHL) of Japan, causing severe abnormalities of bones and the brain. The limb and rib bones are shorter than normal ones, and as regards the brain, abnormalities such as polymicrogyria*1 and periventricular nodular heterotopia (PNH)*2 are discerned. As a gene responsible for TD, fibroblast growth factor receptor 3 (FGFR3) has been reported. However, since it is a rare disease and since it is difficult to obtain brain samples from human patients, the pathophysiology of TD is largely unknown, and effective therapy has not been established.

Concerning the bone abnormalities in TD patients, a team of Kyoto University reported the research results using iPS cells (Nature 2014, 513, 507-511), which attracted much attention. On the other hand, research on abnormalities of the brain has been rather retarded.

The present research team of Kanazawa University succeeded in generating an animal model using ferrets*3, which reproduces the brain abnormalities 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. In the present study, the team has investigated the formation process of PNH, the other brain abnormality found in human TD patients, using their animal model of TD.


The present research team has succeeded in uncovering the pathophysiological process of the formation of PNH by using the TD ferrets as follows.

First, PNH was analyzed in terms of composing cell types to reveal that a large number of neurons but few glial cells*4 existed in PNH. In healthy brain, neurons are found in the cerebral cortex near the brain surface. It was, therefore, considered that during the fetal brain development, PNH formation might be induced by inability of neurons to translocate themselves to their destination, that is, the cerebral cortex. Next, the reason why neurons were unable to translocate themselves was investigated. It was found that spatial arrangement of radial glial cells*5 were distorted; radial glial fibers were considered to serve as the track for neurons to translocate themselves. Thus, it was suggested that the distortion of radial glial fibers would be a reason for aberrant localization of neurons.


The research team elucidated the important process of the PNH formation mechanism. It is only possible, by using appropriate animal model that reproduces relevant pathophysiology, to uncover the process of pathogenesis and to develop therapy. Since the research on abnormalities of bones in TD is progressing with iPS cells at Kyoto University, it is expected that the whole aspect of TD with brain and bone abnormalities would be elucidated and that the therapeutic methods would be developed.

The research team has recognized the importance of disease model animals with the brain architecture more similar to that of humans than mice, a typical model animal, and has been uniquely in the world developing experimental techniques for ferrets, a higher mammal, of Mustelidae. The present study on PNH was only possible with the experimental technique for ferrets developed by the research team. It is expected with the unique experimental technique that research will be carried out further on neurological diseases that have been difficult to investigate with conventional model animal, mouse, and that therapy will be developed in a more accelerated manner.


The surface of the cerebrum has many folds called the gyrus. In the patients of thanatophoric dysplasia (TD), abnormalities of the gyri are seen. More specifically, a larger number of smaller gyri are seen than normal. Hence it is called polymicrogyria.

*2Periventricular nodular heterotopia (PNH)

One of the abnormalities seen in the TD brain is PNH. In normal brain, neurons exist in the cerebral cortex whereas in the brain with TD, some neurons exist in the deep part of the brain as clusters, which are called PNH. The mechanism of PNH formation was largely unknown.


A higher mammal of Mustelidae. Since ferrets have the brain more developed than mice and rather similar to the human brain, ferrets were used as model animal in this study. Genetic research using ferrets are not yet widely carried out in the world, and the present research team is unique in this regard.

*4Glial cells

Most of cells other than neurons in the brain are called glial cells. Glial cells are thought to be important in various functions to support neurons.

*5Radial glia

Radial glia are special cells seen during the period of fetus brain development. They are also referred to as neural stem cells, which develop into neurons and glial cells. In addition, their fibers serve as the track for neurons generated deep in the brain to translocate themselves toward the brain surface.

Kanazawa University

Related Neurons Articles:

How do we get so many different types of neurons in our brain?
SMU (Southern Methodist University) researchers have discovered another layer of complexity in gene expression, which could help explain how we're able to have so many billions of neurons in our brain.
These neurons affect how much you do, or don't, want to eat
University of Arizona researchers have identified a network of neurons that coordinate with other brain regions to influence eating behaviors.
Mood neurons mature during adolescence
Researchers have discovered a mysterious group of neurons in the amygdala -- a key center for emotional processing in the brain -- that stay in an immature, prenatal developmental state throughout childhood.
Astrocytes protect neurons from toxic buildup
Neurons off-load toxic by-products to astrocytes, which process and recycle them.
Connecting neurons in the brain
Leuven researchers uncover new mechanisms of brain development that determine when, where and how strongly distinct brain cells interconnect.
The salt-craving neurons
Pass the potato chips, please! New research discovers neural circuits that regulate craving and satiation for salty tastes.
When neurons are out of shape, antidepressants may not work
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medication for major depressive disorder (MDD), yet scientists still do not understand why the treatment does not work in nearly thirty percent of patients with MDD.
Losing neurons can sometimes not be that bad
Current thinking about Alzheimer's disease is that neuronal cell death in the brain is to blame for the cognitive havoc caused by the disease.
Neurons that fire together, don't always wire together
As the adage goes 'neurons that fire together, wire together,' but a new paper published today in Neuron demonstrates that, in addition to response similarity, projection target also constrains local connectivity.
Scientists accidentally reprogram mature mouse GABA neurons into dopaminergic-like neurons
Attempting to make dopamine-producing neurons out of glial cells in mouse brains, a group of researchers instead converted mature inhibitory neurons into dopaminergic cells.
More Neurons News and Neurons Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#541 Wayfinding
These days when we want to know where we are or how to get where we want to go, most of us will pull out a smart phone with a built-in GPS and map app. Some of us old timers might still use an old school paper map from time to time. But we didn't always used to lean so heavily on maps and technology, and in some remote places of the world some people still navigate and wayfind their way without the aid of these tools... and in some cases do better without them. This week, host Rachelle Saunders...
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at