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Exploring the basic principles of biological phenomena through nematodes

A single fertilized egg repeatedly divides itself to differentiate into a wide variety of cells, such as those forming muscles, nerves, and skin, thus defining the complete body. What happens in the egg to produce the different types of cell?

In studying the mystery of these biological phenomena, Asako Sugimoto, Team Leader of the Laboratory for Developmental Genomics in the Center for Developmental Biology at the RIKEN Kobe Institute, is working on the nematode Caenorhabditis elegans.

The first animal to have its genome decoded completely

When visiting Sugimoto’s laboratory, one is attracted by a line drawing of the nematode C. elegans. A similar illustration also appears on her name card. “The nematode takes only 14 hours from fertilization to hatching, and its embryo and cells are transparent, so one can examine all processes of its body formation in a day”. “I have been studying this organism for more than 15 years, but I never tire of watching it,” says Sugimoto.

It was Sydney Brenner (2002 Nobel Laureate in Medicine) who in the 1960s chose C. elegans as the animal model for his study of the mechanisms behind behavior and development. With a small adult body about 1 mm long, C. elegans occurs in soil everywhere in the world. This organism is suitable for experimentation because it can easily be reared and takes only three days to grow from birth to adulthood. The adult body always contains exactly 959 somatic cells; there are no differences between individuals. The number of cells of each type is also fixed: there are 302 nerve cells. “By fully understanding a simple organism like the nematode, one can elucidate the mechanisms for biological phenomena common to various organisms, including humans.”

For example, nematode research led to a major breakthrough in life science with the discovery of an important biological phenomenon known as apoptosis, a form of cell death in which cells that are no longer necessary commit a form of suicide.

In 1998 the nematode became the first animal to have its genome (the whole of its genetic information) decoded completely. Its genome comprises about 20,000 genes—not significantly different from the number of genes in the human genome, which has been determined as being about 22,000 through the Human Genome Project, completed in 2003. Sugimoto says, “We researchers of nematodes were also astonished by the discovery of the small difference in the number of genes between C. elegans and human beings. Additionally, it was found that 60–70% of the human genes have their counterparts in C. elegans. By examining the roles of the C. elegans genes, one can understand the human genes.”

What is the impact of genome decoding on the life sciences at large? Comparing life to a machine, Sugimoto explains, “Genome decoding can be described as obtaining the whole list of parts of an apparatus, but the roles and mutual connections of the individual parts are not understandable merely from the genome information. The apparatus cannot be assembled nor its actions understood unless the roles and mutual connections of its individual parts are examined.”

To achieve this, some approaches are available. “For example, we gather structurally similar parts and examine their properties and mutual bindability. We also investigate what will happen when a particular part is removed from the apparatus.”

Hence, the role of a particular gene can be estimated from the phenomenon observed when its function is suppressed artificially. Imagine riding on a bicycle with the handlebars removed; the bicycle cannot turn and collides with objects in front of it. In this situation, one realizes that the handlebars are an essential component for changing the direction of the bicycle. Because the list of parts is now available, thanks to the complete decoding of the genome, we are now able to examine all the parts one by one.

In 1998, the very year in which the C. elegans genome was decoded, another major discovery from C. elegans research that represented a breakthrough in life science was reported. This phenomenon is now known as RNA interference. Genetic information written in the DNA is copied to RNA, and protein is produced from this copy. RNA had been thought to be no more than a transmitter of information, but it was found to suppress gene functions. RNA interference has therefore made it possible to perform experiments relatively easily on the suppression of particular genes.

Traditionally, RNA interference experiments had been performed by injecting RNA into a gonad to suppress the function of a target gene in the offspring generation. However, this procedure is very laborious. Sugimoto and her colleagues therefore developed a simple method known as the soaking method. This method induces RNA interference simply by allowing the subject individual to swim in a solution of RNA. Sugimoto explains, “C. elegans is capable of spreading incorporated RNA throughout its whole body. This function is uncommon in other animals. Thus, the new method enables one to apply RNA interference to many nematodes at one time.”

Sugimoto and her colleagues began comprehensively analyzing the genes necessary for the embryogenesis of C. elegans from a fertilized egg to hatching, and for the formation of reproductive cells, with the use of the soaking method. “We classified C. elegans genes by function, using a library kindly supplied by Yuji Kohara, Director of the National Institute of Genetics. We found that 20–25% of the 6,000 genes were essential for embryogenesis, and that suppressing their functions would terminate the development midway.”

Why are different types of cell produced through cell division?

In addition to continuing with a functional analysis of the whole genome, Sugimoto and her colleagues are working to explore the mechanism for cell division from the analytical data. What is the significance of the mechanism for cell division?

“Embryogenesis cannot proceed without an increase in the number of cells by division, resulting in the production of different types of cell. The key to a full understanding of embryogenesis is to know the mechanism for cell division in terms of how these different cell types are produced.”

Cell division does not produce different types of cell unless the cell contents are asymmetrically segregated into the daughter cells. The cell is first polarized, for example into anterior and posterior, with some molecules moving to the anterior side and others to the posterior side. Then the cell divides according to the established polarity to produce two different cells.

In C. elegans, this type of ‘asymmetric cell division’ occurs from the first division of the fertilized egg. The anterior and posterior sides have different destinies: to become somatic (body) cells and the cells that form reproductive (germ) cells, respectively. As this asymmetric division continues, a wide variety of cells are produced. “We are working to explore the basic principle behind embryogenesis by understanding this series of several cell divisions during early embryogenesis.”

Past research has shown that the posterior part is formed on the side where spermatozoon has entered. Why?

The entire cell membrane of the fertilized egg is lined with a mesh structure known as the actin cytoskeleton. On the side where sperm has entered (which will become the posterior part of the body), a hole forms in the mesh, and the entire mesh is pulled toward the opposite side (which is destined to become the anterior part). At the same time, a protein group known as the PAR-3 complex on the mesh migrates forward. As if to fill the broken portion of the mesh, another protein group, PAR-2, covers the superficial layer on the posterior side. Thus PAR-3 and PAR-2 are distributed on the anterior and posterior sides, respectively. Without this pattern of distribution, the fertilized egg could not divide itself into different cell types. “These PAR proteins are known to have an important role in forming different cell types, not only in nematodes but also in other animals.”

Then what triggers the opening of the hole in the mesh? Sugimoto and her colleagues found that a protein known as ECT-2 has a key role. Just after the entry of sperm, ECT-2 is present throughout the superficial layer of the fertilized egg. It begins to disappear from the posterior side, which in turn initiates the opening of a hole in the mesh of the actin cytoskeleton. It is thought that without ECT-2, the mesh structure of the actin cytoskeleton could not be maintained.

Why, then, does ECT-2 disappear from the posterior side? It is the centrosome carried in by the sperm that is crucial in this event. The centromere is a cell organelle essential for cell division, but it is no longer present in the egg. Sugimoto and her colleagues found that if they inhibited the function of a certain gene responsible for the function of the centrosome using RNA interference, ECT-2 was prevented from disappearing from the posterior side. “It seems that some signal is transmitted from the centrosome on the posterior side to ECT-2 to make ECT-2 disappear. We are endeavoring to identify this signal.”

Controlling the assembly of blocks
When a fertilized egg divides, its anterior side becomes a larger cell, which is destined to differentiate into somatic cells, whereas its posterior side becomes a smaller cell and forms the origin of germ cells. To produce this size difference, the mitotic spindle, which halves duplicated chromosome sets, has to be pulled to the posterior side before cell division.

The mitotic spindle consists of microtubules emerging from the two centrosomes on the two poles. Each microtubule extends to the cell’s superficial layer where PAR proteins are present. Because the microtubules in contact with the posterior side, where PAR-2 is present, exert a greater force on the centrosomes than those in contact with the anterior side, where PAR-3 is present, the spindle is pulled to the posterior side. The PAR proteins control the location and motion of the spindle in this way, so that the directions of cell division and the sizes of the resulting individual cells will be determined, but the mechanism of action remains elusive. “We are working to elucidate how the force of the microtubules on the centrosome is regulated by the PAR proteins, by watching the motions of the spindle in detail in three dimensions.”

Each microtubule consists of an assembly of proteins known as tubulin. On completion of cell division, tubulin is disassembled and the spindle is dismantled. In addition to forming the mitotic spindle, the microtubules have diverse functions, including cell morphogenesis and material transport in nerve cells.

“There are many ‘building blocks’ such as actin and tubulin in the cell. According to the type of cell and the stage of cell cycle, these blocks are assembled to form the essential structures, including the actin cytoskeleton and mitotic spindle. How is this assembly controlled? It is quite an interesting research theme,” asserts Sugimoto.

When the spindle is formed, microtubules emerge from the centrosome. “The centrosome is also quite a mysterious organelle. In the center of the centrosome is the centriole, which comprises two cylinders perpendicular to each other. In the cell division phase, the proteins necessary to form microtubules gather around the centrioles. As a result, microtubules emerge from the centrosome to form the spindle.”

Sugimoto and her colleagues are searching for and analyzing genes that hamper the emergence of microtubules from the centrosome or alter the properties of microtubules, by suppressing the functions of particular genes by RNA interference. “Why do the dramatic changes occur in the centrosome at the start of the cell division phase? I want to solve this riddle.”

Mechanisms behind material allocation in the cell
When different cell types are formed during development, the respective essential proteins must be allocated appropriately. It is thought that the PAR proteins are also important in this allocation. For example, when a fertilized egg divides itself, a protein–RNA complex known as germ granules is transported to the posterior side. On the anterior side, where PAR-3 is present, the germ granules are decomposed. The cells on the posterior side, which inherited the germ granules after division, will become germ cells.

As many molecules migrate and are allocated to the anterior or posterior side during cell division, different types of cell are produced. How is traffic control achieved for this migration and allocation? This is one of the greatest riddles in clarifying the mechanism for the production of the different cell types. Of course, different molecules are allocated depending on the type of cell produced. It is conjectured that the molecules to be allocated to the anterior side are marked differently in some way from the molecules to be allocated to the posterior side. “However, these marks have not been identified. More investigations produce more riddles. Much remains unknown, even about the first cell division of the fertilized egg of the simple organism C. elegans.”

Sugimoto is confident, however, that they will make rapid progress in research. “Advances in microscopy and techniques for selectively allowing a particular protein to emit light have made it possible to perform a three-dimensional examination and analysis of the quick, dynamic motions of proteins in individual cells. The technical innovations of the past few years have dramatically increased the number of new insights. I believe that the goal of elucidating the mechanisms for the allocation of materials in the cells will be achieved in the near future by continuing with our current work combining this live-imaging technology with RNA interference. Accelerating the current research will lead to the elucidation of the basic principles behind biological phenomena.”

Nematode research is set to lead to further great discoveries.

About the researcher
Asako Sugimoto received her BSc from the Department of Biophysics and Biochemistry in the University of Tokyo School of Science in 1987, and her doctorate from the same institution in 1992. She worked as a postdoctoral fellow in Joel Rothman's laboratory in the University of Wisconsin – Madison from 1992 to 1996, before returning to Japan to take up an assistant professorship at the University of Tokyo. She remained in that position until 2002, pursuing concurrent work as a Japan Science and Technology Corporation PRESTO researcher from 1997 to 2000. She was appointed team leader at the RIKEN CDB in 2001. Her work seeks to improve the understanding of how an organism’s genome controls dynamic cellular behavior, using Caenorhabditis elegans embryos as a model system.
Asako Sugimoto
Team Leader
Laboratory for Developmental Genomics
Center for Developmental Biology

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