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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

Search PubMed for Yukio Saijoh's Lab Publications

• Nichol, P.F., J.L. Byrne, C. Dodgion, and Y. Saijoh, Clinical considerations in gastroschisis: incremental advances against a congenital anomaly with severe secondary effects. Am J Med Genet C Semin Med Genet, 2008. 148C(3): p. 231-40.
• Park, E.J., X. Sun, P. Nichol, Y. Saijoh, J.F. Martin, and A.M. Moon, System for tamoxifen-inducible expression of cre-recombinase from the Foxa2 locus in mice. Dev Dyn, 2008. 237(2): p. 447-53
• Tanaka, C., Sakuma, R., Nakamura, T., Hamada, H., and Saijoh, Y., Long-range action of Nodal requires interaction with GDF1. Genes Dev, 2007. 21(24): p. 3272-82.
• Bleyl, S.B., Moshrefi, A., Shaw, G.M., Saijoh, Y., Schoenwolf, G.C., Pennacchio, L.A., and Slavotinek, A.M., Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFRalpha reveals rare variants in diaphragmatic hernia patients. Eur J Hum Genet, 2007. 15(9): p. 950-8.
• Oki, S., Hashimoto, R., Okui, Y., Shen, M.M., Mekada, E., Otani, H., Saijoh, Y., and Hamada, H., Sulfated glycosaminoglycans are necessary for Nodal signal transmission from the node to the left lateral plate in the mouse embryo. Development, 2007. 134(21): p. 3893-904.
• Park, E.J., Sun, X., Nichol, P., Saijoh, Y., Martin, J.F., and Moon, A.M., System for tamoxifen-inducible expression of cre-recombinase from the Foxa2 locus in mice. Dev Dyn, 2007.
• Frank, D.U., Elliott, S.A., Park, E.J., Hammond, J., Saijoh, Y., and Moon, A.M., System for inducible expression of cre-recombinase from the Foxa2 locus in endoderm, notochord, and floor plate. Dev Dyn, 2007. 236(4): p. 1085-92.
• Sakamoto, Y., Hara, K., Kanai-Azuma, M., Matsui, T., Miura, Y., Tsunekawa, N., Kurohmaru, M., Saijoh, Y., Koopman, P., and Kanai, Y., Redundant roles of Sox17 and Sox18 in early cardiovascular development of mouse embryos. Biochem Biophys Res Commun, 2007. 360(3): p. 539-44.
• Tsunoda, I., Tanaka, T., Saijoh, Y., and Fujinami, R.S., Targeting inflammatory demyelinating lesions to sites of wallerian degeneration. Am J Pathol, 2007. 171(5): p. 1563-75.
• Decastro M, Saijoh Y, Schoenwlf GC. 2006. Optimized cationic lipid-based gene delivery reagents for use in developing vertebrate embryos. Dev Dyn. 235: 2210-9.
• Takaoka K, Yamamoto M, Shiratori H, Meno M, Rossant J, Saijoh Y, Hamada M.  2006.   The mouse embryo autonomously acquires anterior-posterior polarity at implantation. Dev. Cell 10: 451-9
• Saijoh Y*, Oki S, Tanaka C, Nakamura T, Adachi H, Yan YT, Shen MM, Hamada* H. 2005.  Two nodal-responsive enhancers control left-right asymmetric expression of Nodal. Dev Dyn. 2005:232:1031-6. (*: Corresponding author)
• Yashiro K, Zhao X, Uehara M, Yamashita K, Nishijima M, Nishino J, Saijoh Y, Sakai Y, Hamada H. 2004. Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. Dev Cell. 6(3) :411-22.
• Yamamoto M, Saijoh Y, Perea-Gomez A, Shawlot W, Behringer RR, Ang SL, Hamada H, Meno C. 2004.  Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature. 428: 387-92.
• Hou J, Yashiro K, Okazaki Y, Saijoh Y, Hayashizaki Y, Hamada H. 2004.  Identification of a novel left-right asymmetrically expressed gene in the mouse belonging to the BPI/PLUNC superfamily.  Dev Dyn. 229 :373-9.
• Yamamoto, M., N. Mine, K. Mochida, Y. Sakai, Y. Saijoh, C. Meno, and H. Hamada. 2003. Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Development 130: 1795-804.
• Watanabe, D., Y. Saijoh, S. Nonaka, G. Sasaki, Y. Ikawa, T. Yokoyama, and H. Hamada. 2003. The left-right determinant Inversin is a component of node monocilia and other 9+0 cilia. Development 130: 1725-34.
• Takeuchi, J.K., M. Ohgi, K. Koshiba-Takeuchi, H. Shiratori, I. Sakaki, K. Ogura, Y. Saijoh, and T.  Ogura. 2003. Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis. Development 130: 5953-64.
• Saijoh, Y., S. Oki, S. Ohishi, and H. Hamada. 2003. Left-right patterning of the mouse lateral plate requires nodal produced in the node. Dev Biol 256: 160-72.
• Krebs, L.T., N. Iwai, S. Nonaka, I.C. Welsh, Y. Lan, R. Jiang, Y. Saijoh, T.P. O'Brien, H. Hamada, and T. Gridley. 2003. Notch signaling regulates left-right asymmetry determination by inducing Nodal expression. Genes Dev 17: 1207-12.
• Nonaka, S., H. Shiratori, Y. Saijoh, and H. Hamada. 2002. Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418: 96-9.