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Approach to the Formation of Germ Cells that Transmit Genetic Information to Children
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| How germ cells are formed | |||
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Our body is composed of as many as 60 trillion cells, most of which finish their roles along with the death of the body, excepting for germ cells. "Germ cells are conceptually immortal," says Dr. Nakamura. "Cells can be divided into somatic cells and germ cells. Somatic cells construct the body, and maintain the life of the individual, whereas germ cells differentiate into eggs and sperm and transmit genetic information to the next generation. They are the cells necessary for species to survive. We are advancing our research by using Drosophila, aiming to clarify the mechanism of how germ cells are formed." To begin with, let's look at the flow of how germ cells are formed (Figure 1). An oocyte is interconnected with nurse cells surrounded by somatic follicle cells. The nurse cells produce RNAs and proteins necessary for oogenesis, and they are transported to the oocyte through cytoplasmic bridges called ring canals. "We know that not all RNAs and proteins are distributed uniformly throughout the oocyte, but some of them aggregate at the posterior pole. If this portion is removed, germ cells cannot be formed. The information necessary for germ cell formation localizes at the posterior pole. This specific cytoplasm is called germ plasm." When an oocyte grows into an egg and is fertilized by antherozoid, embryonic development takes place (Figure 1, right). The cells that have taken in the germ plasm at the very early stage of embryonic development become pole cells, which are the only cells that are ordained to develop into germ cells. During subsequent embryogenesis, pole cells migrate into the embryo before they mature in the gonad and become germ cells. "Several proteins localizing in the germ plasm and indispensable for germ cell formation have already been found. However, the actual molecular functions of each protein have remained elusive, and the story from germ plasm to germ cells through pole cells is not linked. We would like to fill out the gap to complete the whole consistent story."  |
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| mRNA translational repression in germ cell formation | |||
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"We know that germ plasm formation begins with the localization of Oskar proteins to the posterior pole of the oocyte. First, please take a look at the mRNA distribution of oskar genes in oogenesis (Figure 2 left, red)," says Dr. Nakamura, presenting a figure. The mRNA is what is transcribed from a part of a gene in a nucleus. When mRNAs are released from a nucleus, their base sequences are translated into a concatenation of amino acids, which results in forming proteins. "You can see that oskar mRNAs are concentrated in the oocyte from the very early stage. However, Oskar proteins localize at the posterior pole of the oocyte only from the middle stage of the oogenesis process (Figure 2 right, arrow). In other words, the translation to proteins is repressed while oskar mRNAs are released from the nuclei of nurse cells and are transported to the posterior pole. Thus, we understand that the mRNA localization to the posterior pole of an egg, and the translational repression during its localization are important for germ plasm formation." It is known that mRNA localization and translational repression are profoundly related to various life phenomena such as the decision of which part becomes the head, back or abdomen. However, the molecular mechanism has remained elusive. Under these circumstances, the Laboratory for Germline Development has discovered important proteins that are related to mRNA translational repression. It is known that translation initiation is generally controlled by the binding of eIF4E, a kind of protein, to the 5'-end of mRNA (Figure 3, left). The Laboratory firstly focused on eIF4E. "We took a biochemical approach to isolate and identify proteins that form a complex with oskar mRNAs, and found the existence of not only eIF4E, but some of those proteins. It was found that among the proteins, a protein named Cup directly binds to eIF4E to repress the translation of oskar mRNAs (Figure 3, right). Furthermore, Cup also binds to another protein Bruno which binds specifically to a region of oskar mRNA. In other words, Cup specifically represses the translation of oskar mRNA by directly binding to both eIF4E and Bruno. A similar translation mechanism in the frog has been reported. However, no similarity in these proteins at the amino acid level was found between frog and Drosophila. This suggests to us that it is not the function of a special protein, but the 'architecture' of the translational repression mechanism that is conserved beyond species." How can these findings be used in the future? "The translation of oskar mRNA must be derepressed after the mRNAs have reached the posterior pole. How does the derepression take place? Right now, this is our biggest concern. We have also found dozens of mutants that exhibit abnormality in germ plasm formation. We expect that finding the causative genes will help us to make an approach to clarify the mechanisms underlying germ plasm formation." It is also known that oskar mRNAs bind to various proteins such as Cup, eIF4E, or Bruno, forming cytoplasmic granules. Thus, attention has been attracted to the granules. "Similar granules have been found in neuronal cells, cultured cells, and budding yeast cells. In neuronal cells, mRNAs migrate to the ends of axial fibers or dendrites, where they are locally translated. This is considered profoundly related to the neuronal plasticity, including memory and learning. Investigation of granule components in neuronal cells shows that the granules are similar to those found in the oogenesis processes." At present, the Laboratory is advancing collaborative research with overseas groups. "Transportation, localization, and translational repression of mRNAs have been observed in various life phenomena. Thus, these are considered universal molecular mechanisms. How people memorize and learn is the biggest question. We believe that our research on germ cells can provide the knowledge about molecular mechanisms."   |
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| Appearance of a new model in cell migration and survival | |||
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There has been a new development regarding germ cell migration. "The mere formation of pole cells does not contribute to germ cell formation. It is only after pole cells have migrated to the gonad that pole cells can differentiate into germ cells (cover page, blue: pole cells migrating in an embryo). We have made interesting findings concerning pole cell migration and survival." It is known that pole cells migrate in an embryo in a manner that avoids the somatic cells in which wunen is expressing, which is a gene that produces lipid phosphate phosphatases (LPPs). LPPs promote the dephosphorylation of special lipid phosphates in the extracellular region and uptake the lipid products into the cells. "It has been simply considered that pole cells hate the environment where the gene wunen is expressing. In fact, if the gene is overexpressed in somatic cells, the pole cells die in the course of migration. However, even in pole cells, we have observed the expression of wunen-2, a special gene that has an activity similar to wunen. Furthermore, pole cells without wunen-2 die in the course of migration." At first, Dr. Nakamura was puzzled because of the contradiction with conventional opinions. Thus he has derived a hypothesis. "It seems necessary for pole cell survival that LPPs dephosphorylate special lipid phosphates outside of the cells and take the lipid products into the cells. Pole cells are likely to avoid somatic cells where the competing gene wunen is expressing, to guarantee taking in the lipid necessary for their survival. Competition between pole cells and somatic cells provides us with a completely new model of cell migration and survival. " LPPs are known to be involved in neurite extension of neuronal cells and blood vessel formation in extra embryonic tissues. Dr. Nakamura says, "This topic will become increasingly interesting." |
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| Sea squirt regenerating germ cells | |||
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The Laboratory for Germline Development has launched a study of Ciona intestinalis, a kind of Chordata. But why the sea squirt? "Like Drosophila, the sea squirt has germ plasm in its eggs. In the normal process of embryonic development, the cells that have taken in the germ plasm can differentiate into germ cells. Drosophila cannot leave offspring when the germ plasm malfunctions, because the embryo cannot produce germ cells. In contrast, the sea squirt is an animal that can regenerate germ cells after metamorphosis, even if its germ cells are removed at the larval stage." Not all living organisms have germ plasm in their eggs. For example, no germ plasm is found in mice and human eggs. In the case of mice or humans, some eggs that receive special signals in the process of embryonic development can develop into germ cells. "The sea squirt is presently the only reported animal that has two mechanisms of germ cell formation, by germ plasm and by epigenetic special signals. We expect that the study on the sea squirt will help us know how both mechanisms experienced changes through the process of evolution." During the interview, Dr. Nakamura said repeatedly, "Our final goal is not only to understand the germ cells of Drosophila, but also to explore the universal principle of life that can be revealed through it." He says with confidence, "We are sure that we can get to the universal principle of life by advancing our own research step by step on what we think interesting." 
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Germ cells are specific cells that transmit genetic information to the next generation, and that stay alive from generation to generation. By using the fruit fly, Drosophila, the Laboratory for Germline Development aims to clarify how germ cells are formed. Preparation for germ cell formation begins during oogenesis that proceeds in the female body of Drosophila. A special region called "germ plasm" is formed in an egg, and only cells that have taken in this germ plasm can develop into germ cells. The Laboratory has succeeded in clarifying in part how the germ plasm is formed. Furthermore, it has been clarified that a mechanism similar to translational repression, which is important in forming germ plasm, functions in neuronal cells, and that the mechanism seems to be involved in memory and learning. Akira Nakamura, Team Leader at the Laboratory, is trying to explore the universal principle that governs living organisms by clarifying the mechanism for the formation of germ cells in Drosophila.