Yasuhiko Kawakami, PhD

Research Techniques:

Mouse genetics, Chick embryo manipulation, Zebrafish transgenesis, In situ hybridization and immunohistochemistry

Research Interests:

The main goal of the Kawakami lab is to understand the mechanisms that regulate normal development of the limb and heart in the vertebrate embryo, and how those mechanisms are re-activated and modified for successful regeneration in adult animals. We use a multi-species approach: mouse, chick and zebrafish, to combine their advantages.

Limb development
Embryonic limbs are first evident as buds that project from the side of the main body axis by proliferation of progenitor cells at the defined axial position. The limb buds undergo outgrowth, patterning and morphogenesis, to construct a stereotypical structure with proper functions. This system provides a unique experimental setting to ask biological questions that also apply to other developmental systems: How do limb buds initiate their development? Do the forelimb (arms) and hindlimb (legs) employ the same mechanisms or distinct mechanisms for their development? What genetic and molecular mechanisms are responsible for regulating spatial and temporal coordination of gene expression and patterning of the limb? How do the forelimb and hindlimb create their distinct structure, while they share common skeletal patterns? What mechanisms are underlying human congenital limb defects?

Our research programs on limb development focus on mechanisms operating on progenitors before limb outgrowth and in early limb bud stage. Such mechanisms involves extracellular stimuli such as FGF, WNT, BMP and hedgehog, as well as transcription factors acting in coordination of extracellular stimuli. A second focus is to understand the mechanisms behind limb defects in human diseases. The lab is focusing on the Sall gene family. Mutations in SALL1 and SALL4 are known to cause human syndromes, the Townes-Brocks and Okihiro syndromes, whose patients show multiple defects, including those in the limb. With mouse genetic approach and chick embryo manipulation, we work to unveil the function of Sall genes during limb development, which will provide insights into the mechanisms behind the limb defects in these human syndromes.

Regeneration of the limb and heart
It has been generally considered that organ regeneration in adults involves re-activation of developmental programs. It remains elusive what molecular, genetic and cellular mechanisms 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. To ask these questions, we use zebrafish as a model animal and the regeneration of the limb (fin) and heart as experimental systems. The regeneration of the fin and heart involves progenitor cell/stem cell maintenance and expansion, and differentiation and pattern formation, topics that may lead to possible applications in tissue engineering. Understanding the mechanisms of organ regeneration is a biological question of significance and importance.

Our fin and heart regeneration projects utilize fluorescent reporter transgenic zebrafish lines. We investigate how genes that regulate critical developmental processes control regeneration of the fin and heart, which would lead to identification of detailed molecular mechanisms of regeneration. We also investigate how pharmacological compounds positively/negatively affect regeneration processes, which potentially leads to identification of materials that may modify regenerative ability and has implications to the development of therapeutic applications.

Selected Publications:

Isaacs M., Kawakami Y., Allendorph G.P., Izpisua Belmonte J. C., and Choe S. (2010) BMP-2 and BMP-6 heterodimer illustrates the nature of ligand-receptor assembly.  Mol. Endocrinol, 24, 1469-1477.

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 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.

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

Raya, A., Consiglio, A., Kawakami, Y., Rodriguez-Esteban, C., and Izpisua Belmonte, J.C.     The zebrafish as a model of heart regeneration      Cloning Stem Cells.  6, 345-351, 2004.

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. (2003). 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.

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

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.

To view these and other publications visit http://www.ncbi.nlm.nih.gov/PubMed
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