Yukio Saijoh
e-mail: y.saijoh@utah.edu
Research Associate 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; Research Associate 1993-1996, Tokyo Metropolitan Institute of Medical Science; Assistant Professor 1996-2004, Osaka University


Pattern formation of vertebrates

My fundamental interest is in vertebrate pattern formation: how vertebrates make up their complicated and organized body plan. Embryogenesis requires correct cell differentiation and positioning of tissues and organs in three dimensions. These two events are closely related to each other and are regulated with respect to each of the three body axes: anterior-posterior, dorso-ventral, and left-right (LR). A goal of my research is to understand the genetic cascade establishing LR asymmetries observed not only in the internal organs of vertebrates such as the heart and stomach but also in the brain function. So far development of LR asymmetry in the brain still remains unsolved but the origin of the asymmetry seems to be the same as in the internal organs. Currently we are focusing on establishment of LR asymmetry in the interanal organs. The genetic cascade establishing initial L-R asymmetry has been identified over the last 10 years, but how LR information regulates asymmetric morphogenesis in internal organs is poorly understood. The goal of my research is to understand the genetic cascade critical for establishing LR asymmetries that is observed in the internal organs of vertebrates such as the heart, stomach and intestines.

Our current emphasis is on studying how LR asymmetry is established in the lateral plate mesoderm that is precursor of internal organs, and how the signals then regulate LR asymmetric morphogenesis in internal organs.

First, we are focusing on the roles of endoderm in establishing LR asymmetry. We have studied mouse Sox17 mutants that have specific initial defects in endoderm cells. This study has revealed that endoderm is important for establishing LR signals before Nodal expression in the lateral plate. We are analyzing molecular mechanisms by which LR asymmetry is regulated by the endoderm cell population.

Second, we are investigating how LR signals regulate asymmetric morphogenesis in heart looping. Cardiac cells derived from the left and right cardiac fields fuse to form a single heart tube and then the tube loops rightward. During heart tube formation and looping, cardiac cells differentiate to start beating. To understand basics of dynamic morphogenesis, we are examining cell behavior during heart tube formation and looping such as cell movement, cell proliferation and cell polarity in the chick system, which is an ideal model to observe heart development in vivo and in culture. Information derived from studies in chicks is used to understand heart looping in mammalian systems, such as the mouse with its valuable genetic tools.

Third, we are interested in intestinal asymmetric morphogenesis using mouse models of human intestine disorders such as malrotation with the same approach as above. Interestingly, intestines develop outside of embryos. The intestines then return into the body just before birth synchronizing with body-wall closure completion. If the timing of these two events is different, intestines are left outside of the body, which causes a congenital disease called omphalocele. Thus, we are investigating body-wall closure morphogenesis together with gut rotaion as a model for human disease ompholocele.

These phenomena in internal organogenesis share the same basic cellular events such as cell proliferation, cell migration, cell to cell adhesion and communication, and cell differentiation. I take several approaches using different model systems to reveal the morphogenesis of LR asymmetry in internal organs.

Selected Publications:

Saijoh, Y., Viotti, M., and Hadjantonakis, A.K. (2014) Follow your gut: relaying information from the site of left-right symmetry breaking in the mouse. Genesis, 52:503-514.

Hou, J., Wei, W., Saund, R.S., Xiang, P., Cunningham, T.J., Yi, Y., Alder, O., Lu, D.Y., Savory, J.G., Krentz, N.A., Montpetit, R., Cullum, R., Hofs, N., Lohnes, D., Humphries, R.K., Yamanaka, Y., Duester, G., Saijoh, Y., and Hoodless, P.A. (2014) A regulatory network controls nephrocan expression and midgut patterning. Development, 141:3772-3781.

Uemura, M., Ozawa, A., Nagata, T., Kurasawa, K., Tsunekawa, N., Nobuhisa, I., Taga, T., Hara, K., Kudo, A., Kawakami, H., Saijoh, Y., Kurohmaru, M., Kanai-Azuma, M., and Kanai, Y. (2013) Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL6 background mice. Development, 140:639-648.

Kosaka, Y., Cieslik, K. A., Li, L., Lezin, G., Maguire, C.T., Saijoh, Y., Toyo-oka, K., Gambello, M.l.J., Vatta, M., Wynshaw-Boris, A., Baldini, A., Yost, H.J., and Brunelli, L. (2012) 14-3-3ε has a role in cardiac ventricular compaction by regulating the cardiomyocyte cell cycle. Mol Cell Biol, 32:5089-5102.

Nichol, P.F., Corliss, R., Yamada, S., Shiota, K., and Saijoh, Y. (2012) Muscle patterning in mouse and human abdominal wall development and ompahlocele specimens of humans. Anat Rec, 295(12):2129-2140.

Saund, R.S., Kanai-Azuma, M., Kanai, Y., Kim, I., Lucero, M.T., and Saijoh, Y. (2012) Gut endoderm is involved in the transfer of left-right asymmetry from the node to the lateral plate mesoderm in the mouse embryo. Development, 139 (13):2426-2435.

Nichol, P.F., Tyrrell, J.D., and Saijoh, Y. (2012) Retinaldehyde dehydrogenase 2 is down-regulated during duodenal atresia formation in Fgfr2IIIb-/- mice. J Surg Res, 175(1):82-87.

Kwan, K.M., Otsuna, H., Kidokoro, H., Carney, K.R., Saijoh, Y., and Chien, C.B. (2012) A complex choreography of cell movements shapes the vertebrate eye. Development, 139(2):359-372.

Nichol, P.F. and Saijoh, Y. (2011) Pitx2 is a critical early regulatory gene in normal cecal development. J Surg Res.

Nichol, P.F., Corliss, R.F., Tyrrell, J.D., Graham, B., Reeder, A., and Saijoh, Y. (2011) Conditional mutation of fibroblast growth factor receptors 1 and 2 results in an omphalocele in mice associated with disruptions in ventral body wall muscle formation. J Pediatr Surg, 46(1):90-96.

Kawasumi, A., Nakamura, T., Iwai, N., Yashiro, K., Saijoh, Y., Belo, J.A., Shiratori, H., and Hamada, H. (2011) Left-right asymmetry in the level of active Nodal protein produced in the node is translated into left-right asymmetry in the lateral plate of mouse embryos. Dev Biol, 353(2):321-330.

Nichol, P.F., Corliss, R.F., Tyrrell, J.D., Graham, B., Reeder, A., and Saijoh, Y. (2011) Conditional mutation of fibroblast growth factor receptors 1 and 2 results in an omphalocele in mice associated with disruptions in ventral body wall muscle formation. J Pediatr Surg, 46(1):90-96.

Bleyl, S.B., Saijoh, Y., Bax, A.M., Gittenberger-de Groot, A.C., Wisse, L.J., Chapman, S.C., Hunter, J., Shiratori, H., Hamada, H., Shiota, K., Klewer, S.E., Leppert, M.F., and Schoenwolf, G.C. (2010) Dysregulation of the PDGF RA gene causes inflow tract anomalies including TAPVR: Integrating evidence from human genetics and model organisms. Hum Mol Genet, 19(7):1286-1301.

Yun, S., Saijoh, Y., Hirokawa, K.E., Kopinke, D., Murtaugh, C.L., Monuki, E.S., and Levine, E.M. (2009) Lhx2 links the intrinsic and extrinsic factors controlling optic cup formation. Development, 36:3895-3906.

Park, E.J., Sun, X., Nichol, P., Saijoh, Y., Martin, J.F., and Moon, A.M. (2008) System for tamoxifen-inducible expression of cre-recombinase from the Foxa2 locus in mice. Dev Dyn, 237(2):447-453.

Tanaka, C., Sakuma, R., Nakamura, T., Hamada, H., and Saijoh, Y. (2007) Long-range action of Nodal requires interaction with GDF1. Genes Dev, 21(24):3272-3282.

Oki, S., Hashimoto, R., Okui, Y., Shen, M.M., Mekada, E., Otani, H., Saijoh, Y., and Hamada, H. (2007) Sulfated glycosaminoglycans are necessary for Nodal signal transmission from the node to the left lateral plate in the mouse embryo. Development, 134(21):3893-3904.

Decastro, M., Saijoh, Y., and Schoenwolf, G.C. (2006) Optimized cationic lipid-based gene delivery reagents for use in developing vertebrate embryos. Dev Dyn, 235:2210-2219.

Takaoka, K., Yamamoto, M., Shiratori, H., Meno, M., Rossant, J., Saijoh, Y., and Hamada, M. (2006) The mouse embryo autonomously acquires anterior-posterior polarity at implantation. Dev. Cell, 10:451-459.

Saijoh, Y., Oki, S., Tanaka, C., Nakamura, T., Adachi, H., Yan, Y.T., Shen, M.M., and Hamada, H. (2005) Two nodal-responsive enhancers control left-right asymmetric expression of Nodal. Dev Dyn, 232:1031-1036.

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.

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.

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.

Nonaka, S., Shiratori, H., Saijoh, Y., and Hamada, H. (2002) Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature, 418:96-99.

Hamada, H., Meno, C., Watanabe, D., and Saijoh, Y. (2002) Establishment of vertebrate left-right asymmetry. Nat Rev Genet, 3:103-113.

Shiratori, H., Sakuma, R., Watanabe, M., Hashiguchi, H., Mochida, K., Sakai, Y., Nishino, J., Saijoh, Y., Whitman, M., and Hamada, H. (2001) Two-step regulation of left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance by Nkx2. Mol Cell, 7:137-149.

Saijoh, Y., Adachi, H., Sakuma, R., Yeo, C.Y., Yashiro, K., Watanabe, M., Hashiguchi, H., Mochida, K., Ohishi, S., Kawabata, M., Miyazono, K., Whitman, M., and Hamada, H. (2000) Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2. Mol Cell, 5:35-47.

Saijoh, Y., Adachi, H., Mochida, K., Ohishi, S., Hirao, A., and Hamada, H. (1999) Distinct transcriptional regulatory mechanisms underlie left-right asymmetric expression of lefty-1 and lefty-2. Genes Dev, 13:259-269.