An extracellular activator of the Drosophila JAK/STAT pathway is a sex-determination signal element

Metazoans use diverse and rapidly evolving mechanisms to determine sex. In Drosophila melanogaster an X-chromosome-counting mechanism determines the s ex of an individual by regulating the master switch gene, Sex-lethal (Sxl)( 1). The X-chromosome dose is communicated to Sxl by a set of X-linked signa l elements (XSEs), which activate transcription of Sxl through its 'establi shment' promoter, Sxl(Pe). Here we describe a new XSE called sisterlessC (s isC) whose mode of action differs from that of previously characterized XSE s, all of which encode transcription factors that activate Sxl(Pe) directly . In contrast, sisC encodes a secreted ligand for the Drosophila Janus kina se (JAK) and 'signal transducer and activator of transcription' (STAT) sign al transduction pathway and is allelic to outstretched (os, also called unp aired). We conclude that sisC works indirectly on Sxl through this signalli ng pathway because mutations in sisC or in the genes encoding Drosophila JA K or STAT reduce expression of Sxl(Pe) similarly. The involvement of os in sex determination confirms that secreted ligands can function in cell-auton omous processes. Unlike sex signals for other organisms, sisC has acquired its sex-specific function while maintaining non-sex-specific roles in devel opment, a characteristic that it shares with all other Drosophila XSEs2.