TMU logo School of Science and Engineering
Department of Biological Sciences
Molecular Neuroscience
Developmental Biology
Cellular Genetics
Molecular Genetics
Plant Development and Physiology
Cellular Biochemistry
Evolutionary Genetics
Plant Environmental Responses
Environmental Microbiology
Animal Ecology
Plant Ecology
Systematic Zoology
Systematic Botany
Photosynthetic Microbial Consortia
Photo Developmental Biology Laboratory
Our laboratory is dedicated to identifying the molecular/genetic basis of the developmental program for chordate embryos and understanding how the developmental program is executed during the course of development from a single cell, fertilized egg to the adult form with functional tissues and organs.
Asc Prof Kimiko Fukuda e-mail
Asc Prof Naohito Takatori e-mail
Hidetoshi Saiga* e-mail
*Visiting Professor
The mechanism involved in differentiation of the digestive tract
Expression of liver marker gene, Hex in the foregut
The digestive tract, which connects between the mouth and the anus, differentiates into various digestive organs. We are interested in the molecular mechanism underlying following topics during development of the digestive tract.
1, Differentiation of the endoderm, which will give rise to gut epithelium.
2, Epithelial folding at the onset of the gut tube formation.
3, Endodermal regionalization, prior to organ differentiation.
4, Boundary formation between two digestive organs.
5, Variation of the digestive organs among species.
Study on the mechanism that segregates mesoderm and endoderm fates in chordate embryos.
The various types of cells that constitute our body is created from a single cell, the fertilized egg. Establishment of the three germ layers, ectoderm, mesoderm and endoderm, is an important early step that is required for the creation of various types of cells. The mechanism that establishes the germ layers have been deeply studied ever since the early days of developmental biology. Recent analysis have shown that mesoderm and endoderm arise from a common ancestor, the mesendoderm cells. However, it is still not understood well how the mesoderm and endoderm fates are separated into different mesendoderm decedent cells.
We are tackling this problem using a marine animal called ascidians (Halocynthia roretzi). Ascidians are sessile filter feeders that spend most of their life attached to objects at the sea bottom, such as rocks and ropes. The opening at the lower left of the animal shown in the photograph is the oral siphon where sea water enters the body. Planktons and organic materials are filtered within the body and the left over sea water leaves through the opening in the upper left, the atrial siphon. The atrial siphon is also used for spawning. Ascidians, surprising for their appearance, is our close relative: ascidians belong to the chordate phylum which includes human, chicks, frogs and fish, but not insects, molluscs or sea urchin. Our favorite animal is not famous, but has many characteristics which have helped us in conducting research.
Our studies have shown that mesoderm and endoderm fates are separated by the following sequence of events. First, mesendoderm cell nucleus moves to the future mesoderm forming side of the cell. mRNA encoding a transcription factor, Not, is transcribed and stored in the nucleus during the migration. The cell enters M-phase when the nucleus is positioned near the mesoderm pole, and Not mRNA is released to the mesoderm side cytoplasm. The mitotic spindle returns to the center of the cell, but Not mRNA remains in the mesoderm side. Not mRNA is partitioned to the mesoderm daughter cell, where it is translated and Not transcription factor suppresses endoderm fate and promotes mesoderm fate. We also found that the direction of nuclear migration is determined by the localization of PI3K and its product, PIP3, to the mesoderm side. We are currently investigating the mechanism that localizes PI3K and PIP3 to the mesoderm side.
Basic developmental program of chordates
Ascidians, lower invertebrate chordates, occupy a peculiar position in the animal phylogeny. Although adult ascidians possess a unique body plan among chordates, their tadpole-shaped larvae, consisting of only 2600 cells, possess a simple chordate body plan.

The development up to the larva proceeds in a very similar way between two ascidian species, Halocynthia roretzi and Ciona intestinalis, which are classified into two distinct groups of the class ascidiacea. Although the two ascidians exhibit a very similar development, their genomes are poorly conserved except for the coding sequences, reflecting their remote phylogenetic distances. Why different genomes make very similar embryos? We are studying to understand transcriptional mechanisms and roles of some key developmental genes in the development of the two ascidians.

Throughout these studies, we are trying to find out what is the basic developmental program of chordates, how it was established and how it has evolved in the lineages to ascidians and other chordates.
Basic developmental program of the digestive tract formation in chordates
In chick embryos, the foregut or hindgut is formed from a sheet of the endodermal tissue. In ascidians, the digestive tract forms from an undifferentiated endodermal cell mass ventrally located in the tadpole trunk.

The digestive tract formation at the initial stage looks quite different between the two animals groups, but in later stages, the esophagus, stomach and gut develop with similar locations along the anterior-posterior axis in the digestive tract. In addition, some developmental genes such as Sox, Cdx and Hox exhibit shared expression patterns along the anterior-posterior axis between the two animals.

We are interested in elucidating the basic developmental program of the digestive tract formation, using the ascidian Ciona intestinalis with a wealth of genomic information and chick embryos with a wealth of experimental embryological information as model systems.
Recent Publications
  1. Kawai, N., Ogura, Y., Ikuta, T., Saiga, H., Hamada, M., Sakuma, T., Yamamoto, T., Satoh, N., and Sasakura, Y. (2015) Hox10-regulated endodermal cell migration is essential for development of the ascidian intestine. Dev. Biol. 403, 43-56.
  2. Oonuma, K., Hirose, D., Takatori, N. and Saiga, H. (2014) Analysis of the transcription regulatory mechanism of Otx during the development of the sensory vesicle in Ciona intestinalis. Zool. Sci. 31, 565-572.
  3. Oonuma, K., Hirose, D., Takatori, N. and Saiga, H. (2014) Continuous expression of Otx in the anterior neural lineage is supported by different transcriptional regulatory mechanisms during the development of Halocynthia roretzi. Dev. Growth & Differ. 56, 189-198.
  4. Nakazawa, K., Yamazawa, T., Moriyama, Y., Ogura Y., Kawai N., Sasakura Y. and Saiga, H. (2013) Formation of the digestive tract in Ciona intestinalis includes two distinct morphogenic processes between its anterior and posterior parts. Dev. Dyn. 242, 1172-1183.
  5. Ikuta, T., Chen, Y.-C., Annunziata, R., Ting, H.-C., Tung, C.-H., Koyanagi, R., Tagawa, K., Humphreys, T., Fujiyama, A., Saiga, H., Satoh, N., Yu, Jr-K., Arnone, M. I. and Su, Y.-H. (2013) Identification of an intact ParaHox cluster with temporal colinearity but residual spatial colinearity in the hemichordate Ptychodera flava. BMC Evol. Biol. (in press)
  6. Freeman, R.F., Ikuta, T., Wu, M., Koyanagi, R., Kawashima, T., Tagawa, K., Humphreys, Fang,G.-C., Fujiyama, A., Saiga, H., Lowe, C., Worley, K., Kirschner, M., Rokshar, D., Satoh, N. and Gerhart, J. (2012) Identical genomic organization of two hemichordate Hox clusters. Curr. Biol. 22, 2053-2058.
  7. Yoshida, K., Ueno, M., Niwano, T. and Saiga, H. (2012) The transcription regulatory mechanism of Pitx in the papilla-forming region in the ascidian, Halocynthia roretzi, implies conserved involvement of Otx as the upstream gene in the adhesive organ development of chordates. Dev. Growth & Differ.54, 649-659.
  8. Yoshida, K. and Saiga, H. (2011) Repression of Rx gene on the left side of the sensory vesicle by Nodal signaling is crucial for right-sided formation of the ocellus photoreceptor in the development of Ciona intestinalis. Dev. Biol. (in press, DOI; 10.1016/j.ydbio.2011.03.006).
  9. Kimura, W., Cantas, A. Sheng, G. Jakt, M., Yasugi, S. and Fukuda, K. (2011) Identification of region specific genes in early chicken endoderm. Gene Exp. Patterns (in press).
  10. Takatori, N., Kumano, G., Saiga, H. and Nishida, H. (2010) Segregation of germ layer fates by nuclear migration-dependent localization of Not mRNA. Dev. Cell 19, 589-598.
  11. Ikuta, T., Satoh, N. and Saiga, H. (2010) Limited functions of Hox genes in the larval development of the ascidian, Ciona intestinalis. Development, 137, 1505-1513.
  12. Kobayashi, M., Takatori, N., Nakajima, Y., Kumano, G., Nishida, H. and Saiga, H. (2010) Spatial and temporal expression of two transcriptional isoforms of Lhx3, a LIM class homeobox gene, during embryogenesis of two phylogenetically remote ascidians, Halocynthia roretzi and Ciona intestinalis. Gene Exp. Patterns, 10, 98-104.
  13. Ikuta, T., Miyamoto, N., Saito Y., Wada, H., Satoh, N. and Saiga, H. (2009) Ambulacrarian prototypical Hox and ParaHox gene complements of the indirect-developing hemichordate Balanoglossus simodensis. Dev. Genes and Evol. 219, 383-389.
  14. Yasuoka, Y., Kobayashi, M., Kurokawa, D., Akasaka, K., Saiga, H. and Taira, M. (2009) Evolutionary roots of blastoporal expression and eorganizerf activity of the vertebrate gastrula organizer gene lhx1 and its ancient metazoan paralog lhx3. Development 136, 2005-2014.
  15. Matsuura, K., Katsumoto, K., Fukuda, K., Kume, K. and Kume. S. (2009) Conserved origin of the ventral pancreas in chicken. Mech Dev. 126, 817-827.
  16. Katsumoto, K., Fukuda, K., Kimura, W., Shimamura, K., Yasugi, S. and Kume, S. (2009) Origin of pancreatic precursors in the chick embryo and the mechanism of endoderm regionalization. Mec. Dev. 126, 539-551
  17. Takatori, N., Butts, T., Candiani, S., Pestarino, M., Ferrier, D.E.K., Saiga, H. and Holland, P.W.H. (2008) Comprehensive survey and classification of homeobox genes in the genome of amphioxus, Branchiostoma floridae. Dev. Genes Evol. 218, 570-590.
  18. Yoshida, K. and Saiga, H. (2008) Left-right asymmetric expression of Pitx is regulated by the asymmetric Nodal signaling through an intronic enhancer in Ciona intestinalis. Dev. Genes Evol. 218, 353-360.
  19. Holland, L.Z., Albalat, R., Azumi,K., Benito-Gutiérrez, E., Blow, M.J., Bronner-Fraser, M., Brunet, F., Butts, T., Candiani, S., Dishaw, L.J., Ferrier, D.E.K., Garcia-Fernàndez, J., Gibson-Brown, J.J., Gissi, C., Godzik, A., Hallböök, F., Hirose, D., Hosomichi, K., Ikuta, T., Inoko, H., Kasahara, M., Kasamatsu, J., Kawashima, T., Kimura, A., Kobayashi, M., Kozmik, Z., Kubokawa,K., Laudet,V., Litman, G.W., McHardy, A.C., Meulemans, D., Nonaka, M., Olinski, R.P., Pancer, Z., Pennacchio, L.A., Pestarino, M., Rast, J.P., Rigoutsos, I., Robinson-Rechavi, M., Roch, G., Saiga, H., Sasakura, Y., Satake, M., Satou, Y., Schubert, M., Sherwood, N., Shiina, T., Takatori, N,, Tello, J., Vopalensky, P., Wada, S., Xu, A., Ye, Y., Yoshida, K., Yoshizaki, F., Jr-Kai, Y., Zhang, Q., Zmasek, C.M., Putnam, N.H., Rokhsar, D.S., Satoh, N. and Holland, P.W.H.(2008) The amphioxus genome illuminates vertebrate origins and cephalochordate biology. Genome Res. 18, 1100-1111.
  20. Takatori, N. and Saiga, H. (2008) Evolution of CUT class homeobox genes: insights from the genome of the amphioxus, Branchiostoma floridae. Int. J. Dev. Biol. 52, 969-977.
  21. Ikuta, T. and Saiga, H. (2007) Dynamic change in the expression of developmental genes in the ascidian central nervous system: revisit to the tripartite model and the origin of the midbrain-hindbrain boundary region. Dev. Biol. 312, 631-643.
  22. Takatori, N., Wada, S. and Saiga, H. (2007) Regionalization of the tail-tip epidermis requires inductive influence from vegetal cells and FGF signaling in the development of an ascidian, Halocynthia roretzi. Zool. Sci. 24, 441-448.
  23. Kimura, W., Yasugi, S. and Fukuda, K. (2007) Regional specification of the endoderm in the early chick embryo. Dev. Growth & Differ. 49, 365-372.
  24. Hojo, M., Takada, I., Kimura, W., Fukuda, K. and Yasugi, S. (2006) Expression patterns of the chicken peroxisome proliferator-activated receptors (PPARs) during the development of the digestive organs. Gene Expression Patterns 6, 171-179.
  25. Shin, M., Noji, S., NeubuNsser, A. and Yasugi, S. (2006) FGF10 is required for cell proliferation and gland formation in the stomach epithelium of the chicken embryo. Dev. Biol. 294, 11-23.
  26. Kimura, W., Yasugi, S., Stern, C. and Fukuda, K. (2006) Fate and plasticity of the endoderm in the early chick embryo. Dev. Biol. 289, 283-295.
  27. Oda-Ishii, I., Bertrand, V., Matsuo, I., Lemaire, P. and Saiga, H. (2005) Making very similar embryos with divergent genomes: conservation of regulatory mechanisms of Otx between the ascidians Halocynthia roretzi and Ciona intestinalis. Development 132, 1663-1674.
  28. Ikuta T. and Saiga, H. (2005) Organization of Hox genes in ascidians: present, past and future. Dev. Dyn. 233, 382-389
  29. Keys, D. N., Lee, B., Di Gregorio, A., Harafuji, N., Detter, J. C., Wang, M., Kahsai, O., Ahn, S., Zhang, C., Doyle, S. A., Satoh, N., Satou, Y., Saiga, H., Christian, A. T., Rokhsar, D. S., Hawkins, T. L., Levine, M. and Richardson, P. M. (2005) A saturation screen for cis-acting regulatory DNA in the Hox genes of Ciona intestinalis. Proc. Natl. Acad. Sci. U.S.A. 102, 679-683.
  30. Matsuda, Y., Wakamatsu, Y., Kohyama, J., Okano, H., Fikuda, K. and Yasugi, S. (2005) Notch signaling functions as a binary switch for the determination of glandular and luminal fates of endodermal epithelium during chicken stomach development. Development 132, 2783-2793.
  31. Asai, R., Okano, H. and Yasugi, S. (2005) Correlation between Musashi-1 and c-hairy-1 expression and cell proliferation activity in the developing intestine and stomach of both chicken and mouse. Dev. Growth & Differ. 47, 501-510.
  32. Hoshino, A., Koide, M., Ono, t. and Yasugi, S. (2005) Sex-specific and left-right asymmetric expression pattern of Bmp7 in the gonad of normal and sex-reversed chicken embryos. Dev. Growth Differ. 47, 65-74.
  33. Hojo, M., Takada, I., Kimura, W., Fukuda, K. and Yasugi, S. (2005) Expression patterns of the chicken peroxisome proliferator-activated receptors (PPARs) during the development of the digestive organs. Gene Expression Patterns 6, 171-179.
  34. Shin, M., Watanuki, K. and Yasugi, S. (2005) Expression of Fgf10 and Fgf receptors during development of the embryonic chicken stomach. Gene Expression Patterns 5, 511-516.
  35. Utsumi, N., Shimojima, Y. and Saiga, H. (2004) Analysis of ascidian Not genes highlights their evolutionarily conserved and derived features of the structure and expression in the development. Dev. Genes Evol. 214, 460-465.
  36. Ikuta, T., Yoshida, N., Satoh, N. and Saiga, H. (2004) Ciona intestinalis Hox gene cluster: its dispersed structure and residual colinear expression in development. Proc. Natl. Acad. Sci. U.S.A. 101, 15118-15123.
  37. Wada, S., Sudou, N. and Saiga, H. (2004) Roles of Hroth, the ascidian otx gene, in the differentiation of the brain (sensory vesicle) and anterior trunk epidermis in the larval development of Halocynthia roretzi. Mech. Dev. 121, 463-474.
  38. Shoguchi, E., Ikuta, T., Yoshizaki, F., Satou, Y., Satoh, N., Asano, K., Saiga, H. and Nishikata, T. (2004) Fluorescent in situ hybridization to ascidian chromosomes. Zool. Sci. 21, 153-157.
  39. Toyoda, R., Kasai, A., Sato, S., Wad,a S., Saiga, H., Ikeo, K., Gojobori, T., Numakunai, T., and Yamamoto, H. (2004) Pigment cell lineage-specific expression activity of the ascidian tyrosinase-related gene. Gene 332, 61-69.
  40. Hiramatsu, H. and Yasugi, S. (2004) Molecular analysis of the determination of developmental fate in the small Intestinal epithelium in the chicken embryo. Int. J. Dev. Biol. 48: 1141-1148.
  41. Oda-Ishii, I. and Saiga, H. (2003) Genomic organization and promoter and transcription regulatory regions for the expression in the anterior brain (sensory vesicle) of Hroth, the otx homologue of the ascidian, Halocynthia roretzi. Dev. Dyn. 227, 104-113.
  42. Endo, Y., Nonaka, M., Saiga, H., Kakinuma, Y., Matsushita, A., Takahashi, M., Matsushita, M. and Fujita, T. (2003) Origin of mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 involved in the lectin complement pathway traced back to the invertebrate, amphioxus. J. Immunol. 170, 4701-4707.
  43. Kobayashi, K., Sawada, K., Yamamoto, H., Wada, S., Saiga, H. and Nishida, H. (2003) Maternal macho-1 is an intrinsic factor that makes cell response to the same FGF signal differ between mesenchyme and notochord induction in ascidian embryos. Development 130, 5179-5190.
  44. Wada, S., Tokuoka, M., Shoguchi, E., Kobayashi, K., Di Gregorio, A., Spagnuolo, A., Branno, M., Kohara, Y., Rokhsar, D., Levine, M., Saiga, H., Satoh, N. and Satou, Y. (2003) A genomewide survey of developmentally relevant genes in Ciona intestinalis II. Genes for homeobox transcription factors. Dev. Genes Evol. 213, 222-234.
  45. Shimizu, Y., Yamamichi, N., Saitoh, K., Watanabe, A., Ito, M., Yamamichi-Nishina, M., Mizutani, M., Yahagi, N., Suzuki, T., Sasakawa, C., Yasugi, S., Ichinose, M. and Iba, H. (2003). Kinetics of v-src-induced epithelial-mesenchymal transition in developing glandular stomach. Oncogene 22, 884-893.
  46. Saito, K., Kawaguchi, A., Kashiwagi, S., Yasugi, S., Ogawa, M. and Miyata, T. (2003) Morphological asymmetry in dividing retinal progenitor cells. Dev. Growth & Differ. 45: 219-229.
  47. Fukuda, K., Kameda, T., Saitoh, K., Iba, H. and Yasugi, S. (2003) Down-regulation of endodermal Shh is required for gland formation in chicken stomach. Mech. Dev. 120: 801-809.
  48. Shin, M., Fukuda, K. and Yasugi, S. (2003) Expression of DDSG1, a novel gene encoding a putative DNA-binding protein in the embryonic chicken nervous system. Mech. Dev. Gene Expression 3, 431-436.
  49. Watanuki, K. and Yasugi, S. (2003) Analysis of transcription regulatory regions of embryonic chicken pepsinogen (ECPg) gene. Dev. Dyn. 228: 51-58.
  50. Wada, S. and Saiga, H.( 2002) HrzicN, a new Zic family gene of ascidians, plays essential roles in the neural tube and notochord development. Development 129, 5597-5608.
  51. Wada, S., Toyoda, R., Yamamoto, H. and Saiga, H. (2002) The ascidian otx gene Hroth activates transcription of a brain specific gene HrTRP. Dev. Dyn. 225, 46-53.
  52. Wang, Y., Zhang, P.J., Yasui, K. and Saiga, H.(2002) Expression of Bblhx3, a LIM-homeobox gene, in the development of amphioxus Branchiostoma belcheri tsingtauense. Mech. Dev. 117, 315-319.
  53. Dehal, P., Satou, Y., Campbell, R.K., Chapman, J., Degnan, B., De Tomaso, A., Davidson, B., Di Gregorio, A., Gelpke, M., Goodstein, D., Harafuji, N., Hastings, K., Ho, I., Hotta, K., Huang, W., Kawashima, T., Lemaire, P., Martinez, D., Meinertzhagen, I. A., Necula, S., Nonaka, M., Putnam, N., Rash, S., Saiga, H., Satake, M., Terry, A., Yamada, L., Wang H.-G., Awazu A., Azumi K., Boore J., Branno M., Chin-bow S., DeSantis R., Doyle, S., Francino, P., Keys, D., Haga, S., Hayashi, H., Hino, K., Imai, K. S., Inaba, K., Kano, S., Kobayashi, K., Kobayashi, M., Lee, B.-I., Makabe, K.W., Manohar, C., Matassi, G., Medina, M., Mochizuki, Y., Mount, S., Morishita, T., Miura, S., Nakayama, A., Nishizaka, S., Nomoto, H., Ohta, F., Oishi, K., Rigoutsos, I., Sano, M., Sasaki, A., Sasakura, Y., Shoguchi, E., Sin-I, T., Spagnuolo, A., Stainier, D., Suzuki, M.M., Tassy, O., Takatori. N., Tokuoka, M., Yagi, K., Yoshizaki, F., Wada, S., Zhang, C., Hyatt, P.D., Larimer, F., Detter, C., Doggett, N., Glavina, T.,Hawkins, T.,Richardson, P., Lucas, S.,Kohara, Y., Levine, M., Satoh N. and Rokhsar, D. (2002) The draft genome of Ciona intestinalis: insights into chordate and vertebrate origins. Science 298, 2157-2167.
  54. Morokuma, J., Ueno, M., Kawanishi H., Saiga, H. and Nishida, H. (2002) HrNodal, the ascidian nodal-related gene is expressed in the left side epidermis, and lies upstream of HrPitx. Dev. Genes Evol. 212, 439-446.
  55. Satoh, G.,Takeuchi, J., Yasui, K., Tagawa, K., Saiga, H., Zhang, P. and Satoh, N.(2002) Amphi-Eomes/Tbr : An amphioxus cognate of vertebrate Eomesodermin and T-Brain1 genes whose expression reveals evolutionarily distinct domain in amphioxus development. J. Exp. Zool. (Mol. Dev. Evol.) 294, 136-145.
  56. Satou, Y., Takatori, N., Fujiwara, S., Nishikata, T., Saiga, H., Kusakabe, T. Shin-I, T., Kohara, Y. and Satoh, N.(2002) Ciona intestinalis cDNA projects: expressed sequence tag analyses and gene expression profiles during embryogenesis. Gene 287, 83-96.
  57. Yasui, K., Li, G., Wang, Y., Saiga, H., Zhang, P. and Aizawa, S. (2002) ƒŔ-catenin in early development of the lancelet embryo implicating a specific determination of the embryonic polarity. Develop. Growth Differ. 44, 467-475.
  58. Fukuda, K. and Yasugi, S. (2002) Versatile roles for sonic hedgehog in gut development. J. Gastroenterol. 37, 239-246.
  59. Matsushita, S., Ishii, Y., Scotting, P. J. and Yasugi, S. (2002). The pre-gut endoderm of chick embryos is regionalized by 1.5 days of development. Dev. Dyn. 223, 33-47.
  60. Yasugi, E., Uemura, I., Kumagai, T., Nishikawa, Y., Yasugi, S.. and Yuo, A. (2002). Disruption of mitochondria is an early event during dolichyl monophosphate-induced apoptosis in U937 cells.@Zool. Sci. 19: 7-13.
  61. Takeda, J., Tabata, H., Fukuda, K. and Yasugi, S. (2002). The involvement of signal transduction pathway mediated by epidermal growth factor receptor in the differentiation of chicken glandular stomach. Dev. Growth & Differ. 44: 501-508
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