Yasuhiko Kawakami, Ph.D.

kawak005@umn.edu

Education and training

Education
Ph.D. at Okayama University, Japan. 1996

Training
Kawasaki Medical School, Japan: 1991-1999
Salk Institute for Biological Studies: 1999-2008

Research Interests
The main goal of the Kawakami lab is to understand molecular and genetic mechanisms regulating organogenesis during embryonic development. A single fertilized egg is a totipotent cell that can give rise to an entire animal body. During embryonic development, cells propagate and differentiate into a variety of cell types. An essential process in creating a body is to organize these cells in a highly coordinated manner to construct different organs with distinct shape and function.

Therefore, the development of embryos can provide an experimental system to study organogenesis. Among a variety of organs, the lab is using the development of the vertebrate limb as a model system. Embryonic limb development has been used as an excellent system to study cell differentiation, cell-cell interaction, signaling pathway cross-talk, and morphogenesis. Considering that limb malformations are one of major birth defects, understanding normal process of limb development is also an important issue to understand genetic causes underlying those defects. Another aspect that the limb can provide is tissue regeneration. A few animal species show extraordinary ability to regenerate lost tissues, while we have very limited ability to regenerate lost tissues. Understanding detailed processes of limb regeneration will provide us with molecular events during tissue regeneration. Such information will be applied to regulate embryonic or adult stem cells and progenitor cells for basic and clinical studies in the future.

Limb development and regeneration
Embryonic limbs are first evident as buds that project from the side of the main body axis by proliferation of limb progenitor cells at the defined axial position. In the following outgrowth process, the limb is patterned along three axes, the proximal-distal, anterior-posterior and dorsal-ventral axes, and form a complex structure with bone, cartilage, muscles, and tendons, with characteristic morphologies. These processes generate forelimbs and hindlimbs, two types of homologous but distinct organs, thereby involving specification of their identity. Studies by myself as well as many other groups have identified key signals, such as WNT, FGF, BMP and Hedgehog, which control vertebrate limb development. However, still little is known about how these regulators function and how cells interpret the signals, leading to proper limb morphogenesis.

It has been generally considered that limb regeneration and limb development follows similar paths, though there are specific and characteristic events during the initial process of regeneration. It remains elusive what molecular, genetic and cellular mechanisms control and which are required in order for proper regeneration to occur. Furthermore, it is largely unknown why some animals, such as salamanders and zebrafish, possess a high ability to regenerate lost tissues, while some animals, such as human and mice, have a very limited ability to regenerate. Understanding the mechanisms of limb regeneration is a biological question of significance and importance.

Both limb development and limb regeneration involve basic and common issues for progenitor cell/stem cell maintenance and expansion, topics that may lead to possible applications in tissue engineering and highlight questions in evolutionary biology. Moreover, a failure to perform the correct actions of the key signaling pathways often causes congenital disorders and diseases, including cancer, in humans. Therefore, the study of limb development and regeneration is also of interest for pathological aspects and clinical applications. 

Selected publication 

• Kawakami Y. , Uchiyama Y., Rodriguez-Esteban C, Inenaga T., Koyano-Nakagawa N., Kawakami H., Marti M., Kmita M., Monaghan-Nichols P., Nishinakamura R, Izpisua Belmonte J.C. Sall genes regulate region-specific morphogenesis in the mouse limb by modulating Hox activities.  Development , 136, 585-594, 2009. 
• Kawakami, Y., Rodriguez Esteban, C., Raya, M., Kawakami, H., Marti, M., Dubova, I.and Izpisúa Belmonte, J.C.  Wnt/beta-catenin signaling regulates vertebrate limb regeneration.   Genes & Development   20, 3232-3237, 2006.
• Kawakami, Y., Rodriguez-Leon, J. and Izpisua Belmonte J.C.   The role of TGF-betas and Sox9 during limb chondrogenesis.   Curr. Opinion Cell Biology 18, 723-729, 2006.
• Oishi, I., Kawakami, Y., Raya, A., Caroll-Massot, C. and Izpisua-Belmonte, J.C.  Regulation of primary cilia formation and left-right patterning in zebrafish by duboraya, a novel mediator of non-canonical Wnt signaling.  Nature Genetics , 38, 1316-1322, 2006.
• Suzuki, A., Raya, A., Kawakami, Y., Morita, M., Matsui, T., Nakashima, K., Gage, F.H., Rodriguez-Esteban, C. and Izpisua Belmonte J.C.  Nanog binds to Smad1 and blocks BMP-induced differentiation of embryonic stem cells.  Proc. Nat. Acad. Sci. U.S.A . 103, 10294-10299, 2006.
• Kawakami, Y., Raya, A., Raya, R. M., Rodríguez-Esteban, C., and Izpisúa Belmonte, J. C.  Retinoic acid signalling links left-right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo.  Nature 435, 165-171, 2005.
• Kawakami, Y ., Tsuda, M., Takahashi, S., Taniguchi, N., Rodríguez Esteban, C., Zemmyo, M., Furumatsu, T., Lotz, M., Izpisúa-Belmonte, J. C., and Asahara, H.   Transcriptional coactivator PGC-1alpha regulates chondrogenesis via association with Sox9. Proc. Nat. Acad. Sci. U.S.A. 102, 2414-2419, 2005.
• Kawakami Y ., Rodriguez Esteban C., Matsui T, Rodriguez Leon J. Koto S., and Izpisua Belmonte J. C. Sp8 and Sp9, two closely related buttonhead-like transcription factors, regulate Fgf8 expression and limb outgrowth in vertebrate embryos.   Development , 131, 4763-4774, 2004.
   
• Kawakami Y ., Rodríguez-León J., Koth C.M., Büscher D., Itoh T., Raya A., Ng J.K., Rodríguez Esteban C., Takahashi S., Henrique D., Schwartz M.F., Asahara H., and Izpisúa Belmonte J.C.   MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb.    Nature Cell Biol . 5, 513-519, 2003.
• Raya A., Koth C.M., Büscher D., Kawakami Y ., Itoh T., Raya M., Sternik G., Tsai H.J., Rodríguez Esteban C., and Izpisúa Belmonte J.C. Activation of Notch signaling pathway precedes heart regeneration in zebrafish.   Proc. Nat. Acad. Sci. U.S.A. 100, Special Supplement on Stem Cells and the Future of Regenerative Medicine,  11889-11895, 2003.
• Ng J.K., Kawakami Y., Büscher D., Raya A., Itoh T., Koth C.M., Rodríguez Esteban C., Rodríguez-León J., Garrity D.M., Fishman M.C., and Izpisúa Belmonte J.C.  The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10.   Development 129, 5161-5170, 2002.
• Kawakami Y., Capdevila J., Buscher D., Itoh T., Rodríguez-Esteban C., and Izpisúa Belmonte J.C. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo.  Cell 104, 891-900, 2001.

Related links
Department of Genetics, Cell Biology and Development, University of Minnesota: http://www.gcd.umn.edu/

Developmental Biology Center, University of Minnesota:
http://www.dbc.umn.edu/

Graduate Program in Molecular, Cellular, Developmental Biology and Genetics
http://mcdbg.umn.edu/