A Conserved Genetic Circuit Governs Invasive Cell Identities and Stem Cell Fates in Drosophila Gametogenesis.

摘要

The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, which is conserved from human to Drosophila melanogaster (fruit fly), is required for proper development and homeostasis. Aberrant activation, however, may result in pathogenesis, including autoimmune diseases and cancer. Thus, pathway activation must be finely tuned. While several endogenous regulators exist, mutations that preclude a proper activation/attenuation cycle may generate a diseased state. If pathogenesis occurs, chemical inhibitors are often utilized to thwart progression of the disease. However, to optimize drug treatments, understanding pathway components is essential. Drosophila are exceptional organisms for these investigations since they are genetically tractable, and a robust array of genetic tools are available. Additionally, Drosophila do not have the complication of redundant proteins in this pathway. Here, we examined the genetic regulation of JAK/STAT in distinct cellular processes. We investigated egg and sperm development (oogenesis and spermatogenesis) and utilized cell migration and stem cell dynamics, respectively, as read-outs for STAT activity. In the developing egg, we discovered the highly conserved protein Suppressor of Cytokine Signaling at 36E (Socs36E) is a required feedback inhibitor of JAK/STAT signaling. Loss of Socs36E partially phenocopied gain of STAT activity: excessive cells acquired invasive properties. We determined that Socs36E attenuates JAK/STAT function via ubiquitin-dependent and additional mechanisms. We, also, present evidence of epigenetic and microRNA regulation of cell motility in the developing egg. These results incorporated Socs36E into a genetic regulatory circuit that is necessary to optimize motile cell number in this tissue. Interestingly, this circuit is conserved in the somatic stem cells of the Drosophila testis. We discovered that the transcriptional regulator Apontic functions as a keystone inhibitor of JAK/STAT activity in the somatic stem cells by regulating two direct pathway inhibitors. Apontic-deficient testes display improper stem cell maturation and an expanded niche---the microenvironment that maintains stem cells. Finally, we utilized chemical genetics to assess JAK/STAT activation upon treatment with a pathway inhibitor using in vitro and ex vivo assays. Collectively, this work utilized a multi-disciplinary approach to understand better the activation/attenuation cycle of the JAK/STAT pathway in distinct cellular processes.