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

Abstract

<italic>Drosophila</italic> 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 <italic>domeless</italic> (<italic>dome</italic>) and <italic>hopscotch</italic> (<italic>hop</italic>) cause precocious disappearance of mushroom body neuroblasts. Further evidence indicates that JAK/STAT signaling prevents neuroblast termination and promotes neuroblast division in <italic>Drosophila</italic> 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.