ZFIN ID: ZDB-LAB-970617-1
Toshio Hirano Lab
Co-PI / Senior
Yamashita, Susumu
Contact Person:
Email: hirano@molonc.med.osaka-u.ac.jp
URL: http://www.med.osaka-u.ac.jp/pub/molonc/www/Eindex.html
Address: Department of Molecular Oncology Graduate School of Medicine Osaka University 2-2, Yamada-oka, Suita Osaka 565-0871 JAPAN
Country: Japan
Phone: 81-6-6879-3880
Fax: 81-6-6879-3889
Line Designation: None assigned



The aim of this research project is to extend further our knowledge and experience obtained from the cytokine research and applied them to elucidation of the mechanisms by which cells of developing zebrafish or mice respond to secreted signaling factors including cytokines to specify cell fate and cell behavior, in particular axis determination, gastrulation, and regionalization. The formation of Spemann organizer is one of the most important steps in dorsoventral axis determination in vertebrate development. We have isolated a novel zebrafish homeobox gene, dharma, specifically expressed in Nieuwkoop center and essential for organizer formation and forebrain formation. The aim of this projects is the elucidation of the molecular mechanisms involved in organizer formation, gastrulation. We will apply the findings in zebrafish to mouse by performing gene-targeting of each responsible gene. The final goal of this project is the application of our findings to the understanding of the molecular mechanisms and control of human diseases.

Previous studies:

Our studies on cell cleavage after fertilaization have revealed that asymmetric p38 activation on one side of the blastodisc required for symmetric and synchronous cleavage (J. Cell Biol. 150:1335-1347, 2000). Our results suggest that dorsal determinants directly or indirectly induce asymmetric p38 activation which seems to be required for cleavage in only future dorsal side. to understand the molecular mechanisms of early development, we have identified several zebrafisf genes, such as dharma, dkk-1, ifez, fezl, pnx, and stat3. Among these two genes that are required for gastrulation, both of which are down stream of maternal Wnt/b-catenin pathway. We found that a novel zebrafish homeobox gene, dharma, which is induced by maternal Wnt/b-catenin pathway and capable of inducing the organizer ectopically (Genes & Development, 12: 2345-2353, 1998). Furthermore, dharma gene was found to be encoded by bozozok locus (Development, 126:1427-1438, 1999), establishing that dharma/bozozok is essential gene for gastrula organiser formation. In fact, dharma/boz and squint/nodal cooperatively induces organizer specific genes, such as goosecoid, chordin and dkk-1 (Mech. of Dev. 91, 293-303, 2000). We also found that Stat3 is activated in the dorsal region in a manner dependent on the maternal Wnt/b-catenin pathway. Most important finding is that Stat3 controls cell movements during gastrulation without affecting early cell fate specification (Developmental Cells, 2: 363-375, 2002).


1. Identification and cloning of molecules involved in dharma-induced organizer formation, forebrain formation and neural development in zebra fish utilizing subtraction, expression cloning and mutagenesis. (zebrafish)

2. Elucidation of the roles of the gp130/JAK /STAT signal transduciton pathway in gastrulation cell movements and identification of the ligand for gp130 and targets genes of the JAK/STAT3 signals involved in cell movements. (zebrafish and mouse)

3. Elucidation of the roles of MAPK, JNK and p38 and upstream signaling molecules related to these MAP kinase family molecules in development. (zebrafish and mouse)

4. Identification of dorsal determinants. (zebrafish)

Hirata, Tsutomu Graduate Student Nojima, Hideaki Graduate Student Yabe, Taijirou Graduate Student

Yabe, T., Hoshijima, K., Yamamoto, T., Takada, S. (2016) Mesp quadruple zebrafish mutant reveals different roles of mesp genes in somite segmentation between mouse and zebrafish. Development (Cambridge, England). 143(15):2842-52
Wanglar, C., Takahashi, J., Yabe, T., Takada, S. (2014) Tbx Protein Level Critical for Clock-Mediated Somite Positioning Is Regulated through Interaction between Tbx and Ripply. PLoS One. 9:e107928
Ge, X., Grotjahn, D., Welch, E., Lyman-Gingerich, J., Holguin, C., Dimitrova, E., Abrams, E.W., Gupta, T., Marlow, F.L., Yabe, T., Adler, A., Mullins, M.C., Pelegri, F. (2014) Hecate/Grip2a acts to reorganize the cytoskeleton in the symmetry-breaking event of embryonic axis induction. PLoS Genetics. 10(6):e1004422
Kimura, T., Nagao, Y., Hashimoto, H., Yamamoto-Shiraishi, Y., Yamamoto, S., Yabe, T., Takada, S., Kinoshita, M., Kuroiwa, A., and Naruse, K. (2014) Leucophores are similar to xanthophores in their specification and differentiation processes in medaka. Proceedings of the National Academy of Sciences of the United States of America. 111(20):7343-7348
Yabe, T., and Takada, S. (2012) Mesogenin causes embryonic mesoderm progenitors to differentiate during development of zebrafish tail somites. Developmental Biology. 370(2):213-222
Nojima, H., Rothhämel, S., Shimizu, T., Kim, C.H., Yonemura, S., Marlow, F.L., and Hibi, M. (2010) Syntabulin, a motor protein linker, controls dorsal determination. Development (Cambridge, England). 137(6):923-933
Bae, Y.K., Kani, S., Shimizu, T., Tanabe, K., Nojima, H., Kimura, Y., Higashijima, S.I., and Hibi, M. (2009) Anatomy of zebrafish cerebellum and screen for mutations affecting its development. Developmental Biology. 330(2):406-426
Yabe, T., Ge, X., Lindeman, R., Nair, S., Runke, G., Mullins, M.C., and Pelegri, F. (2009) The maternal-effect gene cellular island encodes aurora B kinase and is essential for furrow formation in the early zebrafish embryo. PLoS Genetics. 5(6):e1000518
Urven, L.E., Yabe, T., and Pelegri, F. (2006) A role for non-muscle myosin II function in furrow maturation in the early zebrafish embryo. Journal of Cell Science. 119(20):4342-4352
Hirata, T., Nakazawa, M., Yoshihara, S., Miyachi, H., Kitamura, K., Yoshihara, Y., and Hibi, M. (2006) Zinc-finger gene Fez in the olfactory sensory neurons regulates development of the olfactory bulb non-cell-autonomously. Development (Cambridge, England). 133(8):1433-1443
Muraoka, O., Shimizu, T., Yabe, T., Nojima, H., Bae, Y.K., Hashimoto, H., and Hibi, M. (2006) Sizzled controls dorso-ventral polarity by repressing cleavage of the Chordin protein. Nature cell biology. 8(4):329-340
Shimizu, T., Yabe, T., Muraoka, O., Yonemura, S., Aramaki, S., Hatta, K., Bae, Y.K., Nojima, H., and Hibi, M. (2005) E-cadherin is required for gastrulation cell movements in zebrafish. Mechanisms of Development. 122(6):747-763
Miyagi, C., Yamashita, S., Ohba, Y., Yoshizaki, H., Matsuda, M., and Hirano, T. (2004) STAT3 noncell-autonomously controls planar cell polarity during zebrafish convergence and extension. The Journal of cell biology. 166(7):975-981
Bae, Y.K., Shimizu, T., Muraoka, O., Yabe, T., Hirata, T., Nojima, H., Hirano, T., and Hibi, M. (2004) Expression of sax1/nkx1.2 and sax2/nkx1.1 in zebrafish. Gene expression patterns : GEP. 4(4):481-486
Hirata, T., Suda, Y., Nakao, K., Narimatsu, M., Hirano, T., and Hibi, M. (2004) Zinc finger gene fez-like functions in the formation of subplate neurons and thalamocortical axons. Developmental dynamics : an official publication of the American Association of Anatomists. 230(3):546-556
Yamashita, S., Miyagi, C., Fukada, T., Kagara, N., Che, Y.S., and Hirano, T. (2004) Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature. 429(6989):298-302
Nojima, H., Shimizu, T., Kim, C.H., Yabe, T., Bae, Y.K., Muraoka, O., Hirata, T., Chitnis, A., Hirano, T., and Hibi, M. (2004) Genetic evidence for involvement of maternally derived Wnt canonical signaling in dorsal determination in zebrafish. Mechanisms of Development. 121(4):371-386
Yabe, T., Shimizu, T., Muraoka, O., Bae, Y.-K., Hirata, T., Nojima, H., Kawakami, A., Hirano, T., and Hibi, M. (2003) Ogon/Secreted Frizzled functions as a negative feedback regulator of Bmp signaling. Development (Cambridge, England). 130(12):2705-2716
Bae, Y.K., Shimizu, T., Yabe, T., Kim, C.H., Hirata, T., Nojima, H., Muraoka, O., Hirano, T., and Hibi, M. (2003) A homeobox gene, pnx, is involved in the formation of posterior neurons in zebrafish. Development (Cambridge, England). 130(9):1853-1865
Shimizu, T., Yamanaka, Y., Nojima, H., Yabe, T., Hibi, M., and Hirano, T. (2002) A novel repressor-type homeobox gene, ved, is involved in dharma/bozozok-mediated dorsal organizer formation in zebrafish. Mechanisms of Development. 118(1-2):125-38
Yamashita, S., Miyagi, C., Carmany-Rampey, A., Shimizu, T., Fujii, R., Schier, A.F., and Hirano, T. (2002) Stat3 controls cell movements during zebrafish gastrulation. Developmental Cell. 2(3):363-375
Ryu, S.-L., Fujii, R., Yamanaka, Y., Shimizu, T., Yabe, T., Hirata, T., Hibi, M., and Hirano, T. (2001) Regulation of dharma/bozozok by the Wnt Pathway. Developmental Biology. 231(2):397-409
Hashimoto, H., Yabe, T., Hirata, T., Shimizu, T., Bae, Y., Yamanaka, Y., Hirano, T., and Hibi, M. (2000) Expression of the zinc finger gene fez-like in zebrafish forebrain. Mechanisms of Development. 97(1-2):191-195
Fujii, R., Yamashita, S., Hibi, M., and Hirano, T. (2000) Asymmetric p38 activation in zebrafish: Its possible role in symmetric and synchronous cleavage. The Journal of cell biology. 150(6):1335-1347
Hirata, T., Yamanaka, Y., Ryu, S.L., Shimizu, T., Yabe, T., Hibi, M., and Hirano, T. (2000) Novel mix-family homeobox genes in zebrafish and their differential regulation. Biochemical and Biophysical Research Communications. 271(3):603-609
Shimizu, T., Yamanaka, Y., Ryu, S., Hashimoto, H., Yabe, T., Hirata, T., Bae, Y., Hibi, M., and Hirano, T. (2000) Cooperative roles of Bozozok/Dharma and Nodal-related proteins in the formation of the dorsal organizer in zebrafish. Mechanisms of Development. 91(1-2):293-303
Hashimoto, H., Itoh, M., Yamanaka, Y., Yamashita, S., Shimizu, T., Solnica-Krezel, L., Hibi, M., and Hirano, T. (2000) Zebrafish Dkk1 functions in forebrain specification and axial mesendoderm formation. Developmental Biology. 217(1):138-152
Kim, C.-H., Y.-K. Bae, Y. Yamanaka, S. Yamashita, T. Shimizu, R. Fujii, H.-C. Park, S.-Y. Yeo, T.-L. Huh, M. Hibi, and T. Hirano (1997) Overexpression of neurogenin induces ectopic expression of HuC in zebrafish. Neuroscience letters. 239:113-116