[Aug. 25] D5 Medical & Life Science Seminar-Dr. Masahiro Shin

July 2 2021

The "D5 Medical & Life Science Seminar" course will be offered by International Research Center for Medical Sciences (IRCMS). It will run from April 2021 to March 2022, with lectures given by scientists who are affiliated with IRCMS or in collaboration with researchers at IRCMS. The lectures will be given once a month, in English, and by leading scientists in the relevant research field. Students will be taught: 1) how normal physiological functions are maintained in the human body; 2) how these systems become abnormal under certain pathophysiologic conditions; 3) why stem cells are important in animal development and homeostasis; 4) how stem cell-based approaches can help us understand disease mechanisms and find potential cure for diseases related to stem cell malfunction (e.g., cancer, aging).

Date      : August 25, 2021 (Wednesday)

Time      : 10:30 -
              * Zoom online seminar

Speaker : Masahiro Shin, PhD
                Assistant Professor,
                University of Massachusetts Medical School (UMMS)

Title        : Valves are a conserved feature of the zebrafish lymphatic system

Abstract :

    The valves of collecting vessels in the lymphatic system play a crucial role to prevent back-flow of interstitial fluid, thereby maintaining fluid homeostasis. Accordingly, abnormal valve development or function triggers lymph accumulation and causes lymphedema.  Over the past decade, extensive genetic studies using mice have revealed genes required for lymphatic valve development.  However, despite the utility of zebrafish in studying early aspects of lymphatic development, there is no description of lymphatic valves in this model system.

     Here, I discover evidence for a lymphatic valve in the facial lymphatic system of the zebrafish embryo.   1) Electron microscopy revealed morphology of a lymphatic valve that consists of two semilunar valvular leaflets comprising an extra-cellular matrix core covered by a monolayer of lymphatic endothelial cells.   2) Valve-specific markers, gata2a, itga9, foxc1a, nfatc1 and Prox1, were expressed in valve endothelial cells.   3) gata2a and itga9 null zebrafish mutants demonstrated a conserved requirement for the genes in valve formation and fluid homeostasis.   4) We found similar valve defects and lymphedema in embryos mutant for prox1a, nfatc1 and foxc1a.   5) We also identify a conserved cis regulatory element in the gata2a gene capable of driving lymphatic valve endothelial expression.  Zebrafish lacking this regulatory element show endothelial-specific loss of gata2a transcript and lymphatic valve defects linked to lymphedema.   6) Finally, using this enhancer to generate transgenic lines, we performed time-lapse live imaging and in vivo cell labeling to reveal the origins of lymphatic valve progenitors.  Taken together, these observations provide the first evidence of lymphatic valve formation in the zebrafish and demonstrate a conserved genetic pathway is required for this process.

    In the end of seminar, I would like to introduce current progress, including scRNAseq and generation of Cre/lox-mediated conditional knockout zebrafish to find novel markers and gene function in lymphatic valve development using zebrafish model.

Selected publications:

1. Lawson, N. D., Li, R., Shin, M., Grosse, A., Yukselen, O., Stone, O. A., Kucukural, A. and Zhu, L. (2020). An improved zebrafish transcriptome annotation for sensitive and comprehensive detection of cell type-specific genes. eLife 9, e55792.
2. Shin, M., Nozaki, T., Idrizi, F., Isogai, S., Ogasawara, K., Ishida, K., Yuge, S., Roscoe, B., Wolfe, S. A., Fukuhara, S., et al. (2019). Valves Are a Conserved Feature of the Zebrafish Lymphatic System. Dev. Cell 51, 374-386.e5.
3. Liu, P., Luk, K., Shin, M., Idrizi, F., Kwok, S., Roscoe, B., Mintzer, E., Suresh, S., Morrison, K., Frazão, J. B., et al. (2019). Enhanced Cas12a editing in mammalian cells and zebrafish. Nucleic Acids Res. 47, 4169-4180.
4. Shin, M., Male, I., Beane, T. J., Villefranc, J. A., Kok, F. O., Zhu, L. J. and Lawson, N. D. (2016). Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors. Development 143, 3785-3795.

Flyer: (Click for a larger image)