Cell and Developmental Biology University of Michigan

Research

Genetic control of heart development in Drosophila.

Congenital heart disease is the most common type of birth defects, afflicting nearly 1% of newborns. Despite its major impact to human health, causes of congenital heart disease remain largely unknown, due to limited knowledge about genes controlling heart development. Previous studies have demonstrated that genes controlling heart development are highly conserved from Drosophila to human. Drosophila has the simplest heart and the most compact genome, making it an ideal model system to identify and study novel cardiogenic genes at the post-genomic era. During my postdoc training, I have generated a comprehensive GFP marker (Hand-GFP) for the Drosophila heart (Development 2005), and performed the early phase of a large-scale genetic screen by crossing this cardiac-specific GFP transgene to thousands of different mutations. Over the past three years, my group has identified over 50 novel cardiogenic genes. We were able to link a group of these genes to a novel pathways regulating heart development (Science 2006). In parallel, we have been studying highly conserved transcription factors that play crucial roles in heart and muscle development in both Drosophila and vertebrates, such as MRTF and Hand (PNAS 2004; Development 2005; Development 2006), as well as heart and muscle specific microRNAs (PNAS 2005). Current projects in my lab include further characterization of novel cardiac genes identified from the genetic screen, identification of the downstream targets of several highly conserved transcription factors in heart development, as well as studies of heart and muscle specific microRNAs. In parallel, we are continuously carrying out the large-scale genetic screen to a level of genomic saturation. Our long-term goal is to identify all the genes involved in Drosophila heart development, which will allow us to establish a genetic blue-print to illustrate how the heart is built step-by-step through elaborate regulation of gene networks. This blue-print will greatly facilitate our understanding of genetic control of heart development in other model systems, and provide insightful information for developing molecular diagnosis and gene therapies for congenital heart disease. Interested graduate students are encouraged to contact Dr. Han for rotation projects.

• Shanshan Liang
  Graduate Student

Publications

Representative Publications

Han, Z.*, Fujioka, M.*, Su, M., Liu, M., Jaynes, J.B., and Bodmer, R. (2002). Transcriptional Integration of Competence Modulated by Mutual Repression Generates Cell-Type Specificity within the Cardiogenic Mesoderm. Developmental Biology 252, 225-240 (*Co-first author).
• Han, Z., Bodmer, R. (2003). Myogenic cells fates are antagonized by Notch only in asymmetric lineages of the Drosophila heart, with or without cell division. Development 130, 3039-3051.
• Han, Z., Li, X., Wu, J. and Olson, E.N. (2004). A myocardin-related transcription factor regulates activity of serum response factor in Drosophila. Proceedings of the National Academy of Sciences 101, 12567-12572.
• Han, Z., Olson, E.N. (2005). Hand is a direct target of Tinman and GATA factors during Drosophila cardiogenesis and hematopoiesis. Development 132, 3525-3536.
• Fujioka, M., Wessells, R. J., Han, Z., Liu, J., Fitzgerald, K., Yusibova, G. L., Zamora, M., Ruiz-Lozano, P., Bodmer, R., Jaynes, J. B. (2005). Embryonic even-skipped-Dependent Muscle and Heart Cell Fates Are Required for Normal Adult Activity, Heart Function, and Lifespan. Circulation Research 97, 1108-1114.
• Kwon, C.*, Han, Z.*, Olson, E.N., Srivastava, D.  (2005). Drosophila microRNA1 regulates Notch signaling during cardiac lineage determination and differentiation. Proceedings of the National Academy of Sciences 102, 18987-18991 (*Co-first author).
• Han, Z., Yi, P., Li, X., Olson, E.N. (2006). Hand, an evolutionarily conserved bHLH transcription factor required for Drosophila cardiogenesis and hematopoiesis. Development 133 (6): 1175-1182. 
• Yi, P.*, Han, Z.*#, Li, X., Olson, E. N#. (2006). The Mevalonate Pathway Controls Heart Formation in Drosophila by Isoprenylation of G{gamma}1. Science 313 (5791): 1301 – 1303. (*Co-first author and # co-corresponding author).