Identification of the novel Drosophila JAK/STAT pathway target gene chinmo which regulates eye development, tumor formation and stem cell self-renewal

The Drosophila STAT transcription factor Stat92E regulates diverse functions, including organ development and stem cell self-renewal. This pathway is triggered by the phosphorylation of Stat92E by the cytosolic Janus kinase Hopscotch (Hop). Activated Stat92E dimers translocate to the nucleus, where they regulate gene transcription. Hyper-activation of this signaling pathway in the developing eye, blood cells or the adult testis results in an enlarged eye, a lethal fly leukemia due to blood cell tumors, or a testis filled with an increased number of stem cells. In contrast loss-of-function mutations in pathway components lead to the reverse phenotypes. However, the Stat92E target genes that mediate these processes are largely unknown.;Here we report a micro-array analysis which identified 584 genes as potential Stat92E target genes. We first characterized the Serrate gene, which encodes a Notch ligand, and established a negative feedback loop between Notch and JAK/STAT pathways that results in proper growth of this tissue. We then characterized chronologically inappropriate morphogenesis (chinmo). We show that chinmo is autonomously regulated by Stat92E, at least in the developing eye, and mediates a subset of Stat92E's functions. Loss of Stat92E or chinmo function in the eye results in small eyes, excess head cuticle and headless flies. Furthermore, chinmo or Stat92E gain-of-function clones result in the formation of melanotic tumors and lethality. In the adult testis, activated Stat92E is required for the self-renewal of germ-line stem cells (GSCs) and an adult stem cell population called cyst stem cells (CySCs). Although Chinmo is expressed in both GSCs and CySCs, clonal analysis revealed that it is only required for the maintenance of CySCs. These results indicate that Stat92E regulates self-renewal in these two stem cells by regulating different target genes. Finally, we show that over-expression of chinmo in somatic stem cells in the testes is sufficient to induce GSCs expansion, a phenotype similar to the hyper-activation of Stat92E and over-expression of a Stat92E target gene zfh-1. Epistasis anaylsis revealed that Chinmo and Zfh-1 do not regulate each other's expression. Thus, Chinmo and Zfh-1 independently regulate CySCs maintenance and/or inhibition of their differentiation.