JAK/STAT AND HIPPO SIGNALING PATHWAYS INDEPENDENTLY REGULATE THE SAME TARGET GENES TO CONTROL CELL PROLIFERATION

Abstract

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 <italic>yorkie</italic> (<italic>yki</italic>), the downstream effector of the Hippo signaling pathway, efficiently rescues <italic>dome</italic> mutant phenotypes, and overexpression of Yki target-genes <italic>CycE</italic> or/and <italic>Diap1</italic> partially rescues the &#947;-only phenotype that results from lack of JAK/STAT signaling. Further studies indicate that loss of <italic>yki</italic> 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 <italic>CycE</italic> expression in mushroom body neuroblasts via a consensus STAT-binding site. Furthermore, mushroom body neuroblast clones with no <italic>CycE</italic> expression or an excess of <italic>CycE</italic> expression phenocopy mushroom bodies with decreased or increased JAK/STAT signaling activities, respectively. Together these results suggest that <italic>CycE</italic> is transcriptionally regulated by STAT92E and is required for mediating cell proliferation. Moreover, I showed that Stat92E and Yki regulate the transcription of <italic>CycE</italic> by interacting with two independent enhancers.

It is known that the transcription factor <italic>E2f1</italic> is induced by Yki, and my transgenic analysis suggested that two STAT-binding sites are required for <italic>E2f1</italic> expression in <italic>Drosophila</italic> brain and wing disc. Therefore, <italic>E2f1</italic> is another shared target of Stat92E and Yki. Together with the findings of others that <italic>Diap1</italic> is a direct target of STAT92E and Yki, I propose that JAK/STAT and Hippo signaling pathways are integrated to control development of <italic>Drosophila</italic> by independently regulating the transcription of common target genes, such as <italic>CycE</italic> and <italic>E2f1</italic> to control cell proliferation, and <italic>Diap1</italic> to control cell survival.