The InR/Akt/TORC1 Growth-promoting Signaling Negatively Regulates JAK/STAT Activity And Migrators Cell Fate During Morphogenesis

In the course of normal development,one basic and significant biological question is to understand how a particular cell or a group of cells distinguish themselves from other neighboring cells and develop into their final cell type.Border cells in the Drosophila ovary provide a genetically tractable model for elucidating the mechanisms of cell fate determination and cell migration in vivo.Epithelial follicle cells are capable of responding to a gradient of cytokine(Upd),which act as a morphogen to specify border cells and other cell types.This cytokine signaling acts through JAK/STAT pathway.Here,we show that the InR/Akt/TORC1 pathway attenuates the fate determination of migratory border cells.First,loss of Akt or InR or Tor function by genetic mosaic analyses of in anterior follicle cells lead to additional border cells by enhancing the STAT activity.The JAK/STAT signaling pathway plays essential roles in border cell fate determination.It has been demonstrated that a genetic circuit precisely controls the level of STAT activity and thus regulates border cell identity.Both upregulated and downregulated activity of STAT lead to border cell identity and migration defect.Furthermore,we show that protein level of Suppressor of cytokine signaling(SOCS36E)which is a negative regulator of JAK/STAT signaling during border cell specification is decreased in Akt mosaic clones.Similarly,the phenotype of increased STAT activity and decreased SOCS36E protein level were also observed in both InR and TORC1 mutant clones,which are upstream and downstream of Akt,respectively.AFC(Anterior follicular cells)-specific knockdown of Akt,InR,Pdkl and Raptor,which encodes an essential scaffold subunit of the TORC1 respectively result in the same phenotype:excessive border cells are specified.On the contrary,RNAi knock down of the negative regulators including Pten,Tscl and Tsc2 resulted in significant decrease of border cells.Moreover,the phenotype of extra border cells as caused by reduced activity of Akt,InR and TorCl through RNAi knockdown could be rescued by overexpression of SOCS36E in anterior follicular cells simultaneously.In addition,biochemical analysis demonstrates that TORC1 promotes the protein stability of SOCS36E,the conserved negative regulator of JAK/STAT signaling,through physical interaction,suggesting that TORC1 acts as a key regulator coordinating both cell growth and cell differentiation.All of our data indicate the InR/Akt/TORC1 pathway attenuate STAT activity to optimize the number of border cells by stabilizing SOCS36E protein level.It's well known that the InR/Akt/TORC1 pathway mediates the effects of a variety of extracellular signals in a number of cellular processes including cell growth,proliferation,and survival.However,there is no report that the pathway interacts with and regulates JAK/STAT activity in order to specify particular cell type.It requires to be elucidated that how and why metabolism signaling affects morphogen to affect cell specification and whether the interaction between them is conserved.