[Mar. 27] 137th IRCMS Seminar

March 17 2026

We would like to inform you that the 137th IRCMS seminar has been scheduled as below.
* This IRCMS seminar is open to everyone.

Date      : March 27, 2026 (Friday)

Time      : 16:00-17:00

ZOOM　: Meeting ID: 928 8191 9258

　　　　  Passcode:  Sem27Mar

Speaker : Dr. Masahiro Shin (University of Massachusetts Chan Medical School)

Title        : Zebrafish Dissect Vascular Disease

Abstract:

Rasa1 negatively regulates Ras signaling, and its mutation in humans causes pre- and postnatal vascular malformations (VMs) affecting both blood and lymphatic vessels. However, the embryonic origin and progression of these defects remain poorly understood. To define the earliest pathogenic events in lymphatic system, we generated rasa1a-deficient zebrafish using CRISPR, including a frameshift mutation and a floxed allele for cell-specific knockout. On a rasa1b mutant background, rasa1 double-knockout embryos developed lymphedema with valve defect and arrested circulation by 4 days post-fertilization (dpf). Strikingly, loss of rasa1 caused precocious trunk lymphatic vessel formation at 3 dpf in an endothelial cell-autonomous manner. Pharmacological inhibition of Vegfr3/Flt4 or MEK/ERK signaling rescued this phenotype. Using a mosaic knockout strategy, we found that rasa1-deficient endothelial cells in the posterior cardinal vein preferentially contributed to lymphatic vessels. Single-cell RNA sequencing revealed transcriptional changes largely confined to venous endothelial cells, including increased ER stress, RhoA upregulation, and ectopic expression of the lymphatic determinant prox1a. RhoA inhibition prevented excessive lymphatic growth. Time-lapse imaging demonstrated that wild-type lymphovenous progenitors generate asymmetric daughter fates (venous and lymphatic endothelial cells), whereas rasa1-deficient progenitors consistently produced two lymphatic endothelial cells, explaining the expansion of lymphatic endothelium. Together, these findings identify rasa1 as a key regulator of early lymphovenous fate decisions and signaling thresholds that restrict lymphatic vessel growth, providing mechanistic insight into vascular malformation pathogenesis. Ongoing studies are investigating VMs in the brain vasculature to assess the presence of arteriovenous malformations.

Major papers:

1. 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.

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. Developmental Cell 51, 374-386.e5.

3. Shin, M., Yin, H.-M., Shih, Y.-H., Nozaki, T., Portman, D., Toles, B., Kolb, A., Luk, K., Isogai, S., Ishida, K., et al. (2023). Generation and application of endogenously floxed alleles for cell-specific knockout in zebrafish. Developmental Cell 58, 2614-2626.e7.