Jak/stat and Hippo Signaling Pathways Independently Regulate the Same Target Genes to Control Cell Proliferation

Title of Dissertation: JAK/STAT AND HIPPO SIGNALING PATHWAYS INDEPENDENTLY REGULATE THE SAME TARGET GENES TO CONTROL CELL PROLIFERATION Lijuan Du, Doctor of Philosophy, 2014 Dissertation directed by: Professor Jian Wang Department of Entomology University of Maryland Drosophila mushroom bodies, centers of olfactory learning and memory, are generated by four neuroblasts in each brain hemisphere. Through a forward genetic screen, I found that mutations in the Janus Kinase (JAK) / Signal Transducer and Activator of Transcription (STAT) pathway genes domeless (dome) and hopscotch (hop) cause precocious disappearance of mushroom body neuroblasts. Further evidence indicates that JAK/STAT signaling prevents neuroblast termination and promotes neuroblast division in Drosophila mushroom bodies. Remarkably, ectopic expression of yorkie (yki), the downstream effector of the Hippo signaling pathway, efficiently rescues dome mutant phenotypes, and overexpression of Yki target-genes CycE or/and Diap1 partially rescues the γ-only phenotype that results from lack of JAK/STAT signaling. Further studies indicate that loss of yki function causes a similar but less severe phenotype in mushroom bodies, and this phenotype could be rescued by dominant activation of JAK/STAT. I conclude that both JAK/STAT and Yki activities are required for mushroom body neurogenesis, and higher levels of one can compensate for lack of the other. I also found that Stat92E directly controls CycE expression in mushroom body neuroblasts via a consensus STAT-binding site. Furthermore, mushroom body neuroblast clones with no CycE expression or an excess of CycE expression phenocopy mushroom bodies with decreased or increased JAK/STAT signaling activities, respectively. Together these results suggest that CycE is transcriptionally regulated by STAT92E and is required for mediating cell proliferation. Moreover, I showed that Stat92E and Yki regulate the transcription of CycE by interacting with two independent enhancers. It is known that the transcription factor E2f1 is induced by Yki, and my transgenic analysis suggested that two STAT-binding sites are required for E2f1 expression in Drosophila brain and wing disc. Therefore, E2f1 is another shared target of Stat92E and Yki. Together with the findings of others that Diap1 is a direct target of STAT92E and Yki, I propose that JAK/STAT and Hippo signaling pathways are integrated to control development of Drosophila by independently regulating the transcription of common target genes, such as CycE and E2f1 to control cell proliferation, and Diap1 to control cell survival. JAK/STAT AND HIPPO SIGNALING PATHWAYS INDEPENDENTLY REGULATE THE SAME TARGET GENES TO CONTROL CELL PROLIFERATION