Brain Science Institute Brain Science Institute




Pursuing Unknown Genes Involved in the Development of the Brain

Group Director,
Dr.Katsuhiko Mikoshiba


Behavioral disorder in individuals are usually associated with deformities in the corresponding regions of the brain. We can easily find such deformity in the cerebellum because of its unique behavioral abnormality", said Dr. Katsuhiko Mikoshiba, Group Director of the Developmental Brain Science Group, in our interview. Dr. Mikoshiba and his colleagues have discovered various genes involved in the development and differentiation of the brain in their research on the cerebellum. We asked him about the key to the discoveries of these genes and their roles.
Q: Why did you choose the subject "development and differentiation of the Brain". for your research?

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IP3receptor deficient mouse shows combined phenotype of epileptic seizure and cerebellar ataxia(upper)

Blockage of IP3 receptor by an antibody results in conversion of ventralization to dorsalization (lower)

A. The role of organs, such as the heart, the liver or the kidney, is generally to regulate homeostasis in our body; however, the role of the brain is different. In addition to the maintenance of homeostasis, the brain processes and integrates information obtained from the eyes, ears and nose and then expresses its interpretation of the information in various forms of behavior. The particularly important behavioral activities are speaking, listening and seeing. The fact is, we can only communicate verbally and visually among individuals by the brain function; that is to say, the brain is not only an organ but also the human individual him-or herself. Furthermore, by establishing communication among individuals using the brain, we are able to create our culture. Fascinated by the wonder of the brain, I decided to study the brain when I was a student.

Q: What types of molecules have you found?
A. One of them is a protein in the Purkinje cells called P400. In the absence of these cells, the protein is also missing and the animal displays behavioral abnormalities. After over a decade of research, we were able to identify the protein as the IP3 receptor, which is involved in release of Ca2+ from its stores in the cells. We examined the IP3 receptor by various methods such as generating a knock-out mouse by gene targeting technique, and found that the IP3 receptor is essential to fertilization and cell division. Furthermore, IP3 induced Ca2+ release plays an important role in the formation of dorsoventral axis, the extension of neuronal processes and the plasticity of the brain.

Q: You also found several essential proteins.
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Role of Zic (zinc finger protein enriched in the cerebellum)in brain development.
A.Yes. One of these is "Zic". This is a zinc finger protein. The protein is abundant in granule cells of the cerebellum, and we named it "Zic" from, the first two letters of zinc, zi, and, the first letter of cerebellum, c. In fact, the protein is associated with important genes which greatly affect the developmental processes in the brain. Zic became popular, because its homologs were found to be encoded by genes essential to the development of Drosophila (fruit fly), controlling wingless and engrailed genes. There
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Signal cascade for the determination of neuronal positioning
are five types of genes which code for Zic. The type-1 gene affects pattern formation in the cerebellum. Type 2 is the causal gene of 13q syndrome in humans. Type 3 is a gene which determines right and left axis formation. We have demonstrated the function of the type-3 gene recently by reversing the parts of the heart, i.e., the right- side parts being on the left side of the frog, Xenopus laevis. Another gene is responsible for the positioning of neurons. We immunized a Reeler mutant mouse, which has no folds and has disorganized neurons in the cerebellum, against a normal brain tissue. Then, we succeeded in isolating an antibody against a Reeler-gene product for the first time in the world (joint research with Dr. Ogawa, Dr. Nakajima and Dr. Miyata,). Furthermore, we found a new mutant, named the "Yotari" mouse because of its unsteady gait ("yota-ru" in Japanese), which had a genetic disorder designated as Disabled 1. From these findings, the mechanism of neuronal positioning in the brain is well clarified.
Q: What is the key to these findings?
A. We carried out experiments by assuming all possibilities to neveal the mechanism of only one pheno menon. Then, we carefully examined all the data obtained from the experiments to determine if they agreed with the hypotheses initially formulated. When we obtained contradictory experimental results, we consider it as a great opportunity to determine the key to the answers. Finding the Yotari mouse, the IP3 receptor and Zic are good examples.
Q: In conclusion, could you tell us your view of the future of research?
A. If we could clarify the mechanisms which induce development and differentiation of cells in the brain and the functional molecules involved, then we could find the clues to revitalize aged cells and to treat brain diseases. The mechanisms of diseases and aging of cells are, in a way, merely a part of the process of the development and differentiation. I believe that results of our on-going research can be effectively fed back to the medical field. The cerebellum is developed relatively early during evolution and it is an important region for our behavior. This is the reason that the findings in the cerebellum can be a key to solving the mysteries of the entire brain. We will continue pursuing the mechanisms of the cerebellum to find the key to answers.
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