Laboratory of Biomolecular Informatics

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Associate Professor
Tomoya Kitajima
mail tkitajima@cdb.riken.jp
Associate Professor
Hidehiko Inomata
mail hideino@cdb.riken.jp
Fields

Chemical Biology

Belong

Center for Developmental Biology (CDB), RIKEN

Location

Graduate School Affiliates at the CDB

Research Theme

Developmental processes take place through the exchange of information by cells within the constrained spatial environment of the embryo. In our research we will seek to gain a "understanding" into process of pattern formation via morphogen gradient. Further, we are also working to develop methods for "reconstructing" and "controlling" the morphogen gradient in vivo. By using such methods, we hope to gain a deeper understanding of developmental systems. (Inomata)

Chromosome Segregation in oocytes

In order to maintain genetic information across generations, cells must allocate chromosomes equally to daughter cells during mitosis. Meiotic divisions of the mammalian oocyte, however, are known to exhibit a higher frequency of errors in chromosomal segregation than in other cell types. Oocytes formed from such divisions are aneuploid, meaning they have incorrect numbers of chromosomes; if these are fertilized and develop to term, the resulting individual may exhibit congenital anomalies, such as trisomy 21 (Down syndrome). Such errors in chromosomal segregation are also known to increase with the age of the mother, and this risk may be a contributing factor to the low birth rates seen in many developed nations.

Live imaging and genetics in the mouse

Using the mouse as a model, we will seek to conduct detailed and comprehensive analyses of the dynamics of chromosomes and the molecular machinery that underlies chromosome segregation during cell division. We plan to take advantage of the latest live imaging technologies to study the chromosome dynamics of the mouse oocyte at a level detail unprecedented in other cell types. Oocyte chromosomes behave in ways distinct from those in other cells, and these unique dynamics may provide insights into novel mechanisms for chromosome allocation. By combining live imaging with genetics techniques such as RNAi and gene knockouts, we hope to study the mechanisms underlying chromosomal segregation in oocyte meiosis, and identify the causes behind age-related increases in ploidy errors.

Understand the developmental system

Intercellular communication is essential for the formation of a well-ordered body; in its absence, our individual cells would behave in an uncoordinated fashion, and fail to follow the patterns needed for the development of a head, limbs, or other body parts. In our research, we investigate morphogen gradient-dependent pattern formation, using vertebrate (frog, zebrafish) axis formation as a model. In order to ensure that development based on simple concentration gradients is stably reproducible, cell-cell communications mediate by morphogens need to be robust against perturbations. One example of such robustness can be seen in the response of a frog embryo when bisected: such embryos follow normal developmental patterns, despite being half the ordinary size, a phenomenon known as ‘scaling.’ Our team has previously shown how scaling is maintained through morphogen-mediated intercellular communication when the spatial size of the embryo is perturbed. In our lab, we address visualization of morphogen gradients and in vivo imaging along with biochemical approaches to study how developmental robustness is maintained.

Reconstruct and regulate the developmental system

We are also working to develop methods for controlling the shape of morphogen gradients. Gradients are primarily regulated by production, diffusion, and degradation, which indicates that by controlling these factors, it should be possible to arbitrarily design gradients that reconstruct tissue patterns in the embryo. By using such methods, we hope to gain a deeper understanding of developmental systems.

0Chromosome belt in mouse oocytes

1Kinetochore-microtubule attachment

2Quantification of diffusion rate. FRAP assay of mEGFP-tagged protein shown by snapshots (top). Recovery kinetics of mEGFP-tagged proteins (bottom).

3Understand, reconstruct and control the developmental system via morphogen gradient.

Bibliography

Kitajima, T., S., Ohsugi, M., and Ellenberg, J. Complete kinetochore tracking reveals error-prone homologous chromosome biorientation in mammalian oocytes. Cell 146 , 568 - 581 (2011)

Lee, J.*, Kitajima, T. S.*, Tanno, Y., Yoshida, K., Morita, T., Miyano, T., Miyake, M., and Watanabe, Y. Unified mode of centromeric protection by shugoshin in mammalian oocytes and somatic cells. Nature Cell Biology 10 , 42 - 52 (2008)

Kitajima, T. S., Sakuno, T., Ishiguro, K., Iemura, S., Natsume, T., Kawashima, S. A., and Watanabe, Y. Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature 441 , 46 - 52 (2006)

Inomata, H., Shibata, T., Haraguchi, T., and Sasai, Y. Scaling of dorsal-ventral patterning by embryo size-dependent degradation of Spemann's organizer signals. Cell 153 , 1296 - 1311 (2013)

Takai, A., Inomata, H., Arakawa, A., Yakura, M., Matsuo-Takasaki, M., and Sasai, Y. Anterior neural development requires Del1, a matrix-associated protein that attenuates canonical Wnt signaling via the Ror2 pathway. Development 137 , 3293 - 3302 (2010)

Inomata, H., Haraguchi, T., and Sasai, Y. Robust stability of the embryonic axial pattern requires a secreted scaffold for chord in degradation. Cell 134 , 854 - 865 (2008)

Contact

2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
TEL: +81-78-306-0111 / FAX: +81-78-306-0101

Laboratory for Axial Pattern Dynamics
Hidehiko Inomata

Laboratory for Chromosome Segregation
Tomoya Kitajima

http://www.cdb.riken.jp/en/index.html

http://www.cdb.riken.jp/en/index.html