Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Joining the searching for genes that control mind and behavior

01.11.2010
Close collaboration between developmental neurologists and clinical researchers could one day find the genetic answer to what it means to be human.

The highly sophisticated abilities of humans, such as memory, learning, cognition and thought, are achieved in the brain as a result of dramatic evolutionary development. Personality, preference, behavioral patterns, emotion and other mind-related functions also derive from brain functions.

But what genes are responsible for the formation of the human brain and the remarkable abilities of the human mind? Jun Aruga, team leader of the Laboratory for Behavioral and Developmental Disorders at RIKEN’s Brain Science Institute (BSI), is working to identify the genes that play key roles in the brain, and to elucidate their functions by comparing genetic information in various organisms and conducting behavioral experiments in mice. His research is expected to clarify the origins of brain and nerve diseases and lead to the development of new therapies.

ZIC, a gene associated with brain anomalies

“When I was a high-school student, I was fascinated by the psychology books of Freud, Jung and others,” says Aruga. “Soon I became interested in the sophisticated abilities of the human brain, and so chose to study medicine at university.” After graduating from the School of Medicine, he joined the laboratory of Katsuhiko Mikoshiba at the Institute for Protein Research of Osaka University. Mikoshiba himself is now team leader of the Laboratory for Developmental Neurobiology at the BSI. “In those days, a technique for examining genes had just been established. I thought, what are the genes behind the outstanding potential of the human brain? Their functions are surely closely linked to the essential nature of humans. I wanted to identify the functions—that was my motivation for becoming a researcher,” says Aruga.

In Mikoshiba’s laboratory, researchers were studying the formation of the cerebellum, which performs important functions in motor learning and other aspects. “I was responsible for experiments for examining genes expressed in the process of cerebellar formation, and I discovered a gene that was expressed remarkably strongly. I became convinced that it must be important,” says Aruga. His intuition was spot-on. The gene, named ZIC by Aruga and others, proved to play a critical role in the formation of the entire brain, not just the cerebellum.

The formation of the brain begins with the generation of tabular neural tissue known as the neural plate, which undergoes rounding to form a tubular structure called the neural tube. “The rounded neural plate closes in its center, then other portions close like a zipper moving back and forth, resulting in completion of the neural tube closure. One end of the neural tube grows gradually into the complex brain.”

Aruga generated mice that lack the ZIC gene and found that they had malformed neural tubes with incomplete closure of the anterior (forward) or posterior (rearward) end. He also found other malformations, including union of the left and right cerebral ventricles, known as holoprosencephaly, and various cerebellar malformations.

A group of researchers in the USA also subsequently demonstrated through human gene analysis that mutations of the human ZIC gene are associated with holoprosencephaly and cerebellar malformations. “Mutations of the same ZIC gene were found to cause similar brain malformations in humans and mice.” More recently, mutations of the ZIC gene have been shown to cause not only brain malformations, but also anomalies in the left-right positions of internal organs.

SLITRK1, a gene suppressing anxiety/depression susceptibility
The ZIC gene also serves to control the expression of other genes. “Humans and mice have five kinds of ZIC genes. In 2003, we discovered that some of them control the expression of SLITRK.” SLITRK is a gene for a membrane protein that penetrates biomembranes and cell membranes wrapping cell components (organelles). “In the brain, neurons extend neurites—fine filaments called axons or dendrites—to each other to exchange information. The membrane protein produced by SLITRK is structurally similar to the protein involved in the extension of neurites, so I thought this gene must also be important, and continued the research.”

In 2005, a research group in the USA announced that SLITRK1, one of the six SLITRK genes in humans and mice, is associated with Tourette’s syndrome — a disorder, commonly developed in childhood, that causes persistent motor and vocal ‘tics’. It was one of the first discoveries of causal genes for the disease. “We succeeded in preparing mice that lacked the SLITRK1 gene,” says Aruga. “Surprisingly, the mice looked normal at first glance. Mice lacking ZIC have obvious malformations, and many of them die soon after birth. Mice lacking SLITRK1, however, can grow to maturity and females can even bear offspring.”

Aruga and others then decided to conduct behavioral experiments to examine the properties of SLITRK1-deficient mice in detail. “Behavioral experiments are very effective for examining brain functions. We asked the BSI’s Research Resources Center to perform behavioral experiments—they conduct experiments for any laboratory at RIKEN on request, which is very helpful for some of the smaller laboratories because some of the experiments can take up to two months. Kei-ichi Katayama, a fellow researcher in my laboratory, also conducted extensive additional experiments to construct a comprehensive profile of the behavioral abnormalities in mice lacking SLITRK1.”

The behavioral experiments yielded two interesting findings. One was obtained through an experiment in which a mouse is placed in the center of an elevated cross-shaped platform having walls on only one of the two crossed arms. A normal mouse will generally move around the platform to explore its situation. The SLITRK1-deficient mice, however, tended to explore the wall-less limbs less frequently. “Many studies have shown that mice with a tendency for anxiety use the wall-less limb less frequently in this test.”

The other finding came from an experiment in which a mouse is suspended by its tail. Normal mice struggle desperately at first, and soon become still, periodically taking up the struggle again. “The SLITRK1-deficient mice were found to rest in the quiescent state for much longer. They are also known to have a more of a tendency for depression.”

Various other behavioral experiments have revealed that the SLITRK1-deficient mice are highly susceptible to anxiety and depression. Tourette’s syndrome in humans has also been suggested to be associated with a tendency for anxiety and depression.

‘Playing catch’ with clinical researchers

Research then turned to what is happening in the brain of SLITRK1-deficient mice. Niall Murphy, who at the time was serving as a unit leader at the BSI (and who is currently at the University of California), took on the challenge of exploring the neurological effects of SLITRK1 deficiency. “Dr Murphy found that noradrenaline increased in the frontal lobe of the brain in such mice,” says Aruga. Noradrenaline is a neurotransmitter responsible for signaling among neurons and is produced in neurons in a particular region of the brain. These neurons extend neurites throughout the brain and secrete neurotransmitters to regulate the function of the brain as a whole, influencing moods such as comfort and discomfort, and behavioral patterns.

“In behavioral experiments using SLITRK1-deficient mice, clonidine—a drug that regulates noradrenaline—was found to alleviate anxiety. Clonidine is now used as a therapeutic agent for Tourette’s syndrome in humans.” These findings suggest that SLITRK1-deficient mice are useful as an animal model for Tourette’s syndrome and are likely help in elucidating the origins of the disorder, which could lead to the development of new therapies.

“We are right now engaged in an exploratory study using mice and other laboratory animals in a search for genes that are intimately involved in brain formation and functions, like ZIC and SLITRK1. We would then pass any discoveries to clinical researchers, who could examine the relationship between the gene and disease in humans. We would in turn examine in more detail the functions of the gene in laboratory animals on the basis of the clinical information. By ‘playing catch’ with clinical researchers in this way, our research will help to clarify the causes of human diseases and develop therapies.”

Aruga and others have already begun ‘playing catch’ with other groups. “In 2009, a clinical researcher presented a paper reporting on an association between the SLITRK2 gene and manic–depressive psychosis. We generated mice deficient in the gene and examined their behavior. The mice were found to be highly active, and exhibited a tendency similar to mania.”

Joint research with Murphy has shown that SLITRK2-deficient mice have altered serotonin concentrations in the hippocampus and amygdaloid body, areas of the brain related to memory and emotion, respectively. “Since this change in serotonin content is considered to be associated with active behavior, we tried administering lithium and other drugs used to prevent the manic state in human manic–depressive psychosis. But the mania-like tendency was not alleviated. We are now conducting a demonstration study to determine whether the SLITRK2 gene and manic–depressive psychosis are in fact correlated at all.”

More recently, in November 2009, a group of researchers including Aruga, Katayama and Azel Zine from the University of Montpellier in France discovered that the SLITRK6 gene plays a key role in the formation of the sound-sensing neural circuit of the inner ear. “Mice deficient in SLITRK6, generated by Katayama, looked normal in a similar way to the SLITRK1-deficient mice. At that time, Prof. Zine was working in my laboratory as a visiting researcher. Although with us for only two weeks, he astonished us just before returning home by announcing that he had made a discovery in mice lacking the SLITRK6 gene.”

Zine is a researcher who specializes in the inner ear. The cochlea at the heart of the inner ear contains hair cells that sense sound. Neurons extend neurites to the cochlea to transmit the sound information captured by the hair cells to the brain (Fig. 2). “Prof. Zine discovered that the number of neurites in SLITRK6-deficient mice is lower than in normal mice.”

Aruga’s research then allowed the puzzle to be pieced together. During neural circuit formation, the cochlear hair cells produce neurotrophin, a protein that promotes neuron development. This secretion stimulates the growth of neurites. Aruga demonstrated that in SLITRK6-deficient mice, the secretion of neurotrophin is suppressed. “Lower neurotrophin seems to reduce the number of neurites formed. In fact, when we manually applied neurotrophin to ganglial neurons, the number of neurites returned to close to normal levels.” The findings are expected to help in the development of therapies for inner ear dysfunction.

Genome exploration

“The ZIC and SLITRK genes were discovered by intuition and the accumulation of knowledge. We have begun a research project to search for important genes like these by comprehensively and systematically exploring genetic information,” says Aruga. “In the twenty-first century, many projects aimed at decoding the genomes of a wide variety of organisms have been established and many have been completed. When I set up my laboratory at RIKEN in 2004, I wanted to do research using a revolutionary approach that has become possible only recently. I thought it might be possible to identify the genes that are important to the human brain by comparing the genomes of a range of organisms.” Genetic information is written in the arrangement of the four bases (thymine, adenine, guanine and cytosine) in DNA, and the genes of different organisms can be compared on the basis of the similarity of this arrangement. For the ZIC genes, for example (Fig. 3), monkeys are similar to humans in almost all regions. Mice and rats are also similarity in many regions, while chickens, toads and blowfish are similar to humans in only a few regions. The base sequences of these shared regions can therefore be considered to be highly conserved in the process of evolution, and are therefore likely to carry information or functionality that is important for vertebrates.

In his exploration of genomes, Aruga took particular note of the leucine-rich repeat (LRR), part of the structure of membrane proteins (Fig. 4). “Membrane proteins with the LRR structure vary greatly among multicellular animals having nervous systems, such as drosophila and nematodes, with a particularly wide variety in vertebrates. Many LRR-membrane proteins are primarily expressed in brain cells. We conjecture that the LRR structure has played a critical role in the process of evolution that has lead to increased brain size, as in humans.”

In both humans and mice, there are almost 100 membrane proteins with the LRR structure, include some suggested to be associated with psychiatric diseases such as schizophrenia, temporal lobe epilepsy and obsessive–compulsive neurosis. The membrane proteins produced by the SLITRK genes also have the LRR structure. “We are investigating membrane proteins with the LRR structure but with unknown function.”

Aruga’s group is conducting this study while ‘playing catch’ with the BSI’s Laboratory for Molecular Psychiatry, headed by Takeo Yoshikawa, which is pursuing research on the association of human genes and psychiatric diseases. “Prof. Yoshikawa and others are working to determine whether our target genes are related to human psychiatric diseases. Conversely, we are conducting extensive studies to determine whether a genetic mutation found in a patient with psychiatric disease by Yoshikawa is linked to the condition, through behavioral experiments on mice deficient in the gene we have created. We are ‘playing catch’ within the BSI to contribute to medicine. Ultimately, I want to identify a gene that is closely related to the essential nature of being human. I want to find a convincing answer to the question that has fascinated me since I was a high-school student.”

About the Researcher

Jun Aruga

Jun Aruga was born in Tokyo, Japan, in 1962. He graduated from the School of Medicine at Tohoku University in 1987, and obtained his PhD in 1991 from the same institution. After two years as assistant professor at the Institute of Medical Science, University of Tokyo, he joined RIKEN as a research scientist in the Tsukuba Life Science Center. He moved to the RIKEN Brain Science Institute in 1999 and was promoted to laboratory head in 2004. Since then, he has acted as director of his own research group. His research focuses on developmental and behavioral neurobiology based on comparative genomics and analysis of neurological disorder model animals.

Jun Aruga
Team Leader
Laboratory for Behavioral and Developmental Disorders
RIKEN Brain Science Institute

gro-pr | Research asia research news
Further information:
http://www.rikenresearch.riken.jp/eng/frontline/6446
http://www.researchsea.com

More articles from Life Sciences:

nachricht Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Global study of world's beaches shows threat to protected areas

19.07.2018 | Earth Sciences

New creepy, crawly search and rescue robot developed at Ben-Gurion U

19.07.2018 | Power and Electrical Engineering

Metal too 'gummy' to cut? Draw on it with a Sharpie or glue stick, science says

19.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>