Chong Shin, Assistant Professor
Ph.D., Genetics and Development, University of Texas Southwestern Medical Center
Office: Parker H. Petit Biotechnology (IBB) 1313
Generation and regeneration of cells into hepatopancreatic lineages, Bone Morphogenetic Protein (BMP) 2b signaling, Zebrafish genetics, Morphogenesis and organogenesis
Research Overview and Current Research
The overall goal of my research is to understand the molecular and cellular mechanisms that sculpt the differentiation of progenitor and stem cells into specific fates. As an independent investigator, I am delineating the molecular and genetic pathways that program or reprogram cells into a specific lineage, with a primary focus on hepatopancreatic lineages. I use the zebrafish Danio rerio as a model organism, because it allows me to combine a wide range of genetic, cell biological and imaging techniques. These studies will provide invaluable insight to devise strategies for stem cell-based regenerative medicine to treat human diseases such as liver failure and diabetes mellitus.
Which gene regulatory networks are involved in hepatopancreatic cell fate decision?
Understanding how distinct cell types arise from common progenitors is a major quest in developmental biology. Liver and pancreas emerge from a common progenitor-cell population, share similar features of early development, and regulate essential body metabolism. Bmp2b, which is highly expressed in the lateral plate mesoderm, is the ligand for the type I Bmp receptor Alk8 and the key molecule for regulating the liver versus pancreatic fate decision. When Bmp2b was overexpressed, progenitor cells, fated to become pancreas, contributed to the liver. However, the mechanism by which Bmp2b signaling pathways impacts its downstream gene regulatory networks to direct the liver versus pancreas program remains largely unknown. I am identifying the essential players by a detailed microarray analysis. I am also taking advantage of the expression data to establish transgenic fish lines for future chemical mutagenesis screens. Furthermore, signaling activities that act to establish the Bmp2b gradient for proper patterning of hepatopancreatic cells has not been resolved. By candidate approaches, I am uncovering the key factors in this process.
How medial-lateral patterning of endodermal cells translates into anterior-posterior patterning of organs?
Our data showed that the Bmp2b gradient patterns the endodermal cells in a medial (M) to lateral (L) manner at early somite stages: Lateral cells close to the Bmp2b signal differentiate into liver whereas medial cells distant from the signal differentiate into pancreas. However, nothing much is known about how this M-L patterning translates into anterior (A)-posterior (P) identity. This process involves dramatic morphogenetic changes. Tissue morphogenesis represents a fine balance of different cellular processes to rearrange cells' adhesion, shape, and polarity. Using the experimental advantages of zebrafish, I am elucidating two critical aspects, the basic cell biological processes of morphogenesis of liver and pancreas precursors, as well as the underlying genetic pathways controlling them.
What are new molecular players regulating growth and differentiation of liver and pancreas?
Not only the initial specification step but also the subsequent growth and differentiation steps encompass many essential aspects of the cell fate decision process. To further understand these steps, we performed an ENU mutagenesis screen. I selected several mutants that show specific defects in growth and differentiation in endodermal organs. Furthermore, mutants with potential transdifferentiation events (liver to pancreas, pancreas to liver) were detected in this screening scheme. I am continuing to characterize these mutants by performing detailed phenotypic analysis, and through isolating the affected gene by positional cloning.
Anderson, R. M., Bosch, J. A., Goll, M. G., Hesselson, D., Dong, P. D., Shin, D., Chi , N. C., Shin, C. H., Schlegel, A., Halpern, M. and Stainier, D. Y. (2009) Loss of Dnmt1 catalytic activity reveals multiple roles for DNA methylation during pancreas development and regeneration. Developmental Biology 334(1):213-223.
Shin, C. H., Chung, W. -S., Hong, S. -K., Ober, E. A., Verkade, H., Field, H. A. and Stainier, D. Y. (2008) Multiple roles for Med12 in vertebrate endoderm development. Developmental Biology 317 (2): 467-479 (co-corresponding author).
Shin, C. H.* , Chung, W. -S.* and Stainier, D. Y. (2008) Bmp2 signaling regulates the hepatic vs. pancreatic fate decision. Developmental Cell 15(5): 738-748.
Shin, C. H.*, Shin, D.*, Tucker, J., Ober, E. A., Rentzsch, F., Poss, K. D., Hammerschmidt, M., Mullins, M. C., Stainier, D.Y. (2007) Bmp and Fgf signaling are essential for liver specification in zebrafish. Development 134 (11): 2041-2050.
Asanoma, K., Kato, H., Yamaguchi, S., Shin, C. H., Liu, Z. -P., Kato, K., Inoue, T., Miyanari, Y., Yoshikawa, K., Sonoda, K., Fukushima, K. and Wake N. (2007) HOP/NECCI: A novel regulator of mouse trophoblast differentiation. Journal of Biological Chemistry 282 (33): 24065-24074.
Shin, C. H.*, Liu, Z. -P.*, Passier, R.*, Zhang, C. L., Wang, D., Harris, T., Yamagishi, H., Richardson, J., Childs, G. and Olson, E. N. (2002) Modulation of cardiac growth and development by HOP, an unusual homeodomain protein. Cell 110 (6): 725-735.
Wang, D., Passier, R., Liu, Z. -P., Shin, C. H., Wang, Z., Li, S., Sutherland, L.B., Small, E., Krieg, P. and Olson, E. N. (2002) Regulation of cardiac growth and development by SRF and its cofactors. Cold Spring Harbor symposia on quantitative biology 67:97-105.
Shin, C. and Koo, H. -S. (1996) Helical periodicity of GA-alternating triple-stranded DNA. Biochemistry 35(3): 968-972.