My laboratory is interested in understanding how blood vessels form during embryonic development using zebrafish as a model system.
Extensive Research Description
1. Analyzing the
function of Bone Morphogenetic Protein (BMP) signaling during vascular patterning:
During zebrafish development, angiogenesis expands the axial
vessels into a complex vascular network that is necessary for efficient oxygen
delivery. Although the axial artery (dorsal aorta) and the axial vein are
spatially juxtaposed, the initial angiogenic sprouts from these vessels extend in opposite
directions, suggesting that distinct cues may regulate angiogenesis of
the axial vessels. We have recently found
that angiogenic sprouts from the dorsal aorta are dependent on Vegf-A signaling, and do not respond to Bmp
signals. In contrast, sprouts from the
axial vein are regulated by Bmp signaling independent of Vegf-A signals, suggesting that Bmp is a
vein-specific angiogenic cue during early vascular development (Wiley et al, in
press). Our results support a paradigm, whereby different signals
regulate distinct programs of sprouting angiogenesis from the axial vein and
artery, and suggest that signaling heterogeneity contributes to the complexity
of vascular networks. We are currently investigating 1) how venous but not
arterial endothelial cells respond to Bmp signaling, 2) what are the roles of
Bmp signaling in lymphatic development, and 3) how Bmp signaling is transduced
within endothelial cells.
2. Investigating interaction between endothelial and hematopoietic lineages during development: It has been hypothesized that endothelial and hematopoietic lineages are closely related during development. For instance, these two lineages share common precursor population, the hemangioblasts. Using the combination of single cell labeling and lineage tracing, we have shown that the hemangioblasts exist during development (Vogeli et al, 2006). We have also shown that Notch signaling is essential in modulating the number of the endothelial progenitors. Inhibition of Notch signaling increases the number of endothelial cells by three folds at the expense of hematopoietic stem cells, suggesting that Notch signaling pathway promote hematopoietic stem cell fate over endothelial cell fate in early development (Lee et al, 2009). Later in development, we have recently made an observation that both arterial and venous endothelial cells are capable of generating cmyb positive hematopoietic stem cells, presumably via asymmetric cell division. To better understand how the endothelial lineage contributes to the hematopoietic lineage later in development, we are currently investigating 1) how asymmetric cell division might regulate the number of hematopoietic stem cells, 2) how plane of cell division regulates the emergence of hematopoietic stem cells from the endothelial cells, and 3) what are the roles of environmental factors such as hemodynamic forces on the formation of hematopoietic stem cells from the endothelial lineage.
3. Analyzing molecular and cellular defects of vascular specific mutations: From recently completed screen, several mutations affecting vascular development have been identified (Jin et al, 2007). Using flk1:EGFP transgenic lines which expresses GFP in all endothelial cells, we categorized these mutations into four classes: mutations affecting angioblast specification, mutations affecting vascular tube formation, mutations affecting angiogenesis and remodeling process, and mutations affecting maintenance of vasculature. Among these, we are interested in first two classes of mutations. Currently, all mutations are mapped on the respective linkage groups. We will pursue positional cloning of the aforementioned mutants, and analyze their phenotype with molecular, genetic, and biochemical approaches to understand the functions of the loci affected by these mutations during vascular development.
- Kim, J.-D., Kang, H., Larrivée, B., Lee, M.Y., Mettlen, M., Schmid, S.L., Qyang, Y., Eichmann, A. and Jin, S.W. (2012) Context Dependent Pro-Angiogenic Function of Bone Morphogenetic Protein Signaling is Mediated by Disabled Homolog 2, Dev. Cell, 23:441-44
- Wiley, D.M., Kim, J.D., Hao, J, Hong, C.C., Bautch, V.L.*, and Jin, S.W.* (2011) Distinct Signaling Pathways Regulate Sprouting Angiogenesis from the Dorsal Aorta and Axial Vein, Nat. Cell. Biol. 13, 686–692 (*: Co-corresponding authors)
- Lee, C.Y*., Vogeli, K.M.*, Kim, S.H., Chong, S.W., Jiang, Y.J., Stainier, D.Y., and Jin, S.W. (2009) Notch signaling functions as a cell-fate switch between the endothelial and hematopoietic lineages. Curr Biol. 19(19): 1616-22. (*: Co-first author)
- Jin, S.W.*, Herzog, W.*, Santoro, M.M., Mitchell, T.S., Frantsve, J., Jungblut, B., Beis, D., Scott, I.C., D'Amico, L.A., Ober, E.A., Verkade, H., Field, H.A., Chi, N.C., Wehman, A.M., Baier, H., and Stainier, D.Y.* (2007) A transgene-assisted genetic screen identifies essential regulators of vascular development in vertebrate embryos. Dev Biol. 307(1): 29-42. (*: Co-corresponding authors)
- Vogeli, K.M.*, Jin, S.W.*, Martin, G.R., and Stainier, D.Y. (2006) A common progenitor for haematopoietic and endothelial lineages in the zebrafish gastrula. Nature. 443(7109): 337-9. (*: co-first authors)
- Jin, S.W., Beis, D., Chen, J.N., Mitchell, T.S., and Stainier, D.Y.R. (2005), Cellular and molecular analyses of vascular tube and lumen formation in zebrafish, Development, 132(23):5199-209.