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Professor

Toshihiko OGURA

Assistant Professor

Yusuke WATANABE

Assistant Professor

Kota MIYASAKA

Most important progress in the fields of modern biology and medicine is the complete sequencing and decoding of genomes of several animal including human. Efficient processing of vast amount of genetic Information makes it possible to retrieve it and perform in silico analyses. Using this approach, we are now standing at a new entrance to an unexplored world of biology.

Exploiting this, we have found that we human beings share the same sets of genetic program even with Dosophila. For example, Drosophila Hox genes exert the same biological functions in mammalian embryos and vice a versa. This indicates that comparative analyses of several decoded genomic informations could be a powerful approach to identify the key genetic programs that control orchestrated development of vertebrate embryos.

Based on these pivotal findings, we have identified several important genes that act as critical factors during morphogenesis of embryo. Tbx5 and Tbx4 (human homologue of Drosophila omtomotor blind gene) are expressed in the fore- and hindlimb, respectively. We already reported that forced expression of Tbx5 in the chick hindlimb (leg) induces forelimb-like transformation and Tbx4 in the chick forelimb (wing) converts it morphology to the leg-like one. These data suggest that Tbx5 and Tbx4 are the critical determinant of the wing (forelimb)/leg (hindlimb) identity of tetrapod limbs. Interestingly, we also found that forced expression of Tbx5 and Tbx4 in the flank (between the wing and leg) induces formation of additional wing and leg, respectively. This suggests that Tbx5 and Tbx4 genes specify the identity of limb buds and also more importantly act as bona fide Initiators of limb outgrowth. In addition, we have reported that Tbx5, which is expressed also in the dorsal side of developing retina, control pattern formation of eye and the retinotectum projection along the dorsal-ventral axis of retina. Consequently, our data suggest that Tbx5 gene control pattern formation of the eye and also the neural network between the retina and the chick primary visual center tectum.

Recently we have found that Tbx5 is expressed in the left ventricle of developing heart, and another Tbx gene, Tbx20, in the right ventricle, hence making a complementary expression in the ventricle. Our preliminary data suggest that Tbx5 and Tbx20 specify the identites of left/right ventricles and the position of the ventricular septum to separate the aortic and pulmonary circulation.

To explore the mechanism of cerebellum development, we isolated several Irx genes (vertebrate homologues of Drosophila iroquous genes). One of them, Irx2, is expressed in the rhombic lip (the prospective cerebellum) at the rostral hindbrain. Performing extensive studies, we have found that Irx2 protein is phophorylated by MAP kinase, which is a downstream target of FGF8, an organizer expressed in the isthmus. Surprisingly, misexpression of Irx2 and Fgf8 genes in the midbrain induces complete transformation of tectum to cerebellum, indicating that Irx2 acts as a determinant of cerebellum development, functioning along with the FGF signaling cascade (Figure). Since six Irx genes are found in vertebrates and expressed in region-specific manners in developing brain, our preliminary data suggest that each Irx gene controls differentiation of distinct populations of neurons distributed in region-specific fashions.

As mentioned above, comparative analyses of genetic information could be a powerful tool to identify new genes that plays essential roles during embryogenesis. Exploiting these approaches, we aim to reveal the common and universal sets of genetic program that governs the pattern formation of vertebrate embryos, especially in the field of developmental neurobiology. As a final goal, we want to answer one of simple but essential questions, how our human brain develops complex and distinct neural networks and how we human beings have evolved.

Tectum-to-cerebellum transformation by Irx2 misexpression

Publication list

1. Jun K. Takeuchi, Kazuko Koshiba-Takeuchi, Takayuki Suzuki, Mika Kamimura, Keiko Ogura and Toshihiko Ogura
   Tbx5 and Tbx4 trigger limb initiation through activation of the WNT/FGF signaling cascade.
   Development 130ÅA2729-2739 (2003)
2. Toshihiko Ogura (invited review)
   In vivo electroporation: a new frontier for gene delivery and embryology.
   Differentiation 70, 163-171 (2002)
3. Keiko Ogura, Ken Matsumoto, Asato Kuroiwa, Taku Isobe, Takao Otoguro, Vesna Jurecic, Antonio Baldini, Yoichi Matsuda and Toshihiko Ogura
   Cloning and chromosomal mapping of human and chicken iroquois (Irx) genes.
   Cytogenetics and Cell Genetics 92, 320-325 (2001)
4. Kazuko Koshiba-Takeuchi, Jun K. Takeuchi, Ken Matsumoto, Tsuyoshi Momose, Kenichiro Uno, Veit Hoepker, Keiko Ogura, Harukazu Nakamura, Kunio Yasuda, and Toshihiko Ogura.
   Tbx5 and the retinotectum projection.
   Science 287ÅA134-137 (2000)
5. un K. Takeuchi, Kazuko Koshiba-Takeuchi, Ken Matsumoto, Astrid Vogel-Hopker A, Mayumi Naitoh-Matsuo, Keiko Ogura, Kunio Yasuda, Toshihiko Ogura.
   Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds.
   Nature 398, 810-814 (1999)
6. Motohisa Takahashi, Koji Tamura, Dirk Buscher, Hiroshi Masuya, Sayuri Yonei-Tamura, Ken Matsumoto, Mayumi Naitoh-Matsuo, Jun Takeuchi, Keiko Ogura, Toshihiko Shiroishi, Toshihiko Ogura, Juan Carlos Izpisua Belmonte
   The role of Alx-4 in the establishment of anteroposterior polarity during vertebrate limb development.
   Development 125, 4417-4425 (1998)