In multicellular organisms, cells communicate with each other through biochemical cascades known as signaling pathways. Being one of these pathways, Wnt signaling is repetitively used throughout animal development as well as in adult tissue regeneration and stem cell maintenance. Misregulation of Wnt signaling has been connected to several cancers, bone disease and metabolic disorders. While Wnt signaling has been studied for more than 30 years, many unanswered questions remain about how it influences cell fate and behavior. For instance, there has been considerable progress on understanding the basic mechanisms of how Wnt signaling regulates the transcription of its targets but how this pathway regulates different genes in distinct tissues/cell types is still poorly understood.
My thesis work addressed the question of how Wnt signaling diversity is achieved by examining the Wnt-dependent regulation of Tiggrin (Tig), an essential Drosophila gene encoding an extracellular matrix protein. Unlike the vast majority of Wnt targets, which are activated by the pathway, Tig is directly repressed by Wnt stimulation. The first project of my thesis intended to better understand the mechanism of this repression. I discovered non-tranditional DNA motifs in a cis-regulatory module from the Tig locus that mediate Wnt-repression in the Drosophila hematopoietic system through bipartite recognition by TCF, the major transcription factor of the pathway. When swapped with the classic TCF binding sites, I found that the quality of TCF binding sites dictates the type of transcriptional output, i.e. activation or repression, likely through allosteric regulation of TCF. This work provides a paradigm for diversity in Wnt signaling and basic transcriptional regulation. The second project of my thesis describes the role of Tig in influencing hematopoiesis in Drosophila larva. I found that the Wee1 kinase, which slows G2/M progression, inhibits maturation of a major lineage of Drosophila immune cells through activation of Tig. This work elucidates connections between cell cycle regulators, the extracellular matrix and hematopoiesis.PHDMolecular, Cellular and Developmental BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/133313/1/chenzh_1.pd
