We use zebrafish to investigate the molecular mechanisms by which diverse and specialized cell types are developed during the vertebrate embryogenesis. Currently, our laboratory is particularly interested in three areas. First, we are working to define the genetic pathways underlying hematopoiesis and vasculargenesis. We are especially interested in identifying those factors that mediate the initial determination of hemangioblast and its subsequent differentiation into blood and vascular lineage-specific progenitor cells. Genetic, transgenic and microarray approaches have been used to identify and characterize these key factors. Secondly, we are studying the genetic basis underlying organ formation. The main focus of this research is to understand the genes and cells that direct pancreatic organogenesis. To this end, a number of zebrafish mutations affecting development of pancreas and endocrine beta cells have been isolated. There is a great need to be able to grow and develop pancreatic beta cells for treating diabetes by cell transplantation. This need challenges us to understand how a precursor cell gives rise to the pancreas and to characterize the gene products that specify cell fates during organogenesis. Finally, we are developing new technologies, such as genetic knockout and high throughput transgenesis, for zebrafish in order to better address fundamental questions raised in our biological studies. We have already developed a streamlined procedure of directly selecting multiple bacterial artificial chromosome (BAC) clones based on public sequence database followed by rapid modification with GFP or RFP. BAC constructs offer greater fidelity in directing desirable expression of transgenes. Application of this technology in the transparent zebrafish embryos with the fluorescent protein reporter genes enables unparalleled visual analysis of gene expression in a living organism. A large-scale analysis of gene regulation using BAC transgenesis and comparative genomics approaches is currently ongoing in the laboratory. We plan to analyze hundreds of highly conserved developmental and disease genes from human, mouse, rat and zebrafish to reveal their common regulatory cis-acting elements and validate them in transgenic zebrafish. Given that developmental programs are well conserved among vertebrate animals, our studies in zebrafish should ultimately lead to a better understanding of the molecular and genetic basis underlying human development.
Huang H, Lindgren A, Wu X, Liu NA, Lin S., "High-throughput screening for bioactive molecules using primary cell culture of transgenic zebrafish embryos", Cell Rep, 2 (3): 695-704 (2012) .
Zhang Y, Morimoto K, Danilova N, Zhang B, Lin S., "Zebrafish models for dyskeratosis congenita reveal critical roles of p53 activation contributing to hematopoietic defects through RNA processing", PLoS One, 7 (1): e30188- (2012) .
Veldman MB, Lin S., "Etsrp/Etv2 is directly regulated by Foxc1a/b in the zebrafish angioblast", Circ Res, 110 (2): 220-229 (2012) .
Gomez G, Lee JH, Veldman MB, Lu J, Xiao X, Lin S., "Identification of vascular and hematopoietic genes downstream of etsrp by deep sequencing in zebrafish", PLoS One, 7 (3): e31658- (2012) .
Huang P, Xiao A, Zhou M, Zhu Z, Lin S, Zhang B., "Heritable gene targeting in zebrafish using customized TALENs", Nat Biotechnol, 29 (8): 699-700 (2011) .
Tehrani Z, Lin S., "Antagonistic interactions of hedgehog, Bmp and retinoic acid signals control zebrafish endocrine pancreas development", Development, 138 (4): 631-640 (2011) .
Danilova N, Sakamoto KM, Lin S., "Ribosomal protein L11 mutation in zebrafish leads to haematopoietic and metabolic defects", Br J Haematol, 152 (2): 217-228 (2011) .
Zhong H, Wang D, Wang N, Rios Y, Huang H, Li S, Wu X, Lin S., "Combinatory action of VEGFR2 and MAP kinase pathways maintains endothelial-cell integrity", Cell Res, 21 (7): 1080-1087 (2011) .
Ren X, Gomez GA, Zhang B, and Lin S., "Scl isoforms act downstream of etsrp to specify angioblasts and definitive hematopoietic stem cells", Blood, 15 (26): 5338-5346 (2010) .
Danilova, N., Sakamoto, K. and Lin, S., "Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family", Blood, 12 (13): 5228-5237 (2008) .