YUKIO SAIJOH

Yukio Saijoh
email: y.saijoh@utah.edu		 Assistant Professor of Neurobiology and Anatomy

Developmental Neuroscience

B.S. 1986, Tohuku University; M.S 1988, Tohuku University; Ph.D. 1991, Tohuku University; Postdoctoral fellow 1991-1993, Mitsubishi Kasei Institute of Life Sciences; Postdoctoral fellow 1993-1996, Tokyo Metropolitan Institute of Medical Science; Assistant Professor 1996-2004, Osaka University

RESEARCH:

Dr. Saijoh's interest is in pattern formation of vertebrates, how vertebrate make up their complicated and organized body pattern. He focuses on establishment of Left-Right (L-R) asymmetry because it is one of three important axis information (AP, DV and LR) in establishing body plan. His present research focuses on L-R asymmetric morphogenesis observed in many internal organs in vertebrates such as the heart and stomach. The L-R asymmetric morphogenesis depends on L-R information that is established at early somite stage of development. My question is how left-right information regulates asymmetric morphogenesis in the heart and stomach. To address this question, he takes several approaches using different model systems.

Cardiac myocytes derived from left and right cardiac field fuse to form symmetric single heart tube and then the tube loops rightward. First, to understand the dynamic morphogenesis during heart looping toward right, cell behavior during heart looping morphogenesis is investigated by use of cell tracing experiments using dye injection experiment in chick system, which is ideal model to observe their development in vitro.

Addition to chick experiments, mice are also used to trace cells in heart morphognesis because of their strong genetic tools. We have many mutant mice that showed laterality defects such as randomization, situs inversus, and left and right isomerisms. To gain insight into how L-R signals regulate asymmetric morphogenesis, cell movement in normal and mutant mouse embryos is traced in whole embryo culture system. Addition to dye injection method, we examine transgenic mice that express fluorescence protein such as GFP driven by L-R asymmetric enhancer and heart cell specific enhancer.

When breaks are made in anterior boundary of the heart fields, left and right heart tubes fail to fuse and form independent left and right hearts with different morphology. This separated hearts in the chick embryo are good system to investigate difference left and right heart. Analysis of gene expression and cell behavior will reveal how left and right heart tube develop their difference in heart looping morphogenesis.

He also investigates genetic cascade involved in the asymmetric morphogenesis. Nodal, a member of TGF-beta superfamily, is the initial determinant of L-R asymmetry and induce expression of Pitx2 homeobox transcription factor, which is known to be the only downstream gene of Nodal signal in L-R determination so far. Interestingly, Pitx2 mutants, however, showed normal orientation of heart looping. Therefore, it is essential to investigate downstream genes of Nodal signal. We are now planning differential screening between left and right heart tube. The separated hearts in the chick is good system to investigate difference left and right heart.

Finally, we also investigate how genetic cascade underlies cardiac myocytes differentiation during asymmetric heart morphogenesis. Asymmetric expression of Nodal gene occurs for short period of time during development. Therefore, timing between differentiation of cardiac myocytes and induction of left-right signal is important. Although outline of genetic cascade in heart cell differentiation have been reported, we do no know details during the differentiation. P19CL6 cell line, which is a subline of P19 embryonic carcinoma stem cells, shows efficient differentiation into beating cardiac myocytes after induction by DMSO. Using the system, genetic cascade during heart cell differentiation and influence of Nodal signal on heart cells will be investigated.

Selected Publications

Yashiro, K., Zhao, X., Uehara, M., Yamashita, K., Nishijima, M., Nishino, J., Saijoh, Y., Sakai, Y., and Hamada, H. (2004) Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. Dev Cell, 6(3):411-422.

Yamamoto, M., Saijoh, Y., Perea-Gomez, A., Shawlot, W., Behringer, R. R., Ang, S. L., Hamada, H., and Meno, C. (2004) Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature, 428:387-392.

Hou, J., Yashiro, K., Okazaki, Y., Saijoh, Y., Hayashizaki, Y., and Hamada, H. (2004) Identification of a novel left-right asymmetrically expressed gene in the mouse belonging to the BPI/PLUNC superfamily. Dev Dyn., 229:373-379.

Yamamoto, M., Mine, N., Mochida, K., Sakai. Y., Saijoh, Y., Meno, C., and Hamada, H. (2003) Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Development, 130:1795-1804.

Watanabe, D., Saijoh, Y., Nonaka, S., Sasaki, G., Ikawa, Y., Yokoyama, T., and Hamada, H. (2003) The left-right determinant Inversin is a component of node monocilia and other 9+0 cilia. Development, 130:1725-1734.

Takeuchi, J. K., Ohgi, M., Koshiba-Takeuchi, K., Shiratori,, H., Sakaki, I., Ogura, K., Saijoh, Y., and Ogura, T. (2003) Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis. Development, 130:5953-5964.

Saijoh, Y., Oki, S., Ohishi, S., and Hamada, H. (2003) Left-right patterning of the mouse lateral plate requires nodal produced in the node. Dev Biol, 256:160-172.

Krebs, L. T., Iwai, N., Nonaka, S., Welsh, I. C., Lan, Y., Jiang, R., Saijoh, Y., O'Brien, T. P., Hamada, H., and Gridley, T. (2003) Notch signaling regulates left-right asymmetry determination by inducing Nodal expression. Genes Dev, 17:1207-1212.

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