Cell type specificity of negative regulators: Sprouty and Argos, and their modulation by Seven-up in eye development. M. Iwanami ^1,2, M. Okabe ^1,3, Y. Hiromi ^1,3. 1) Division of Developmental Genetics, National Inst. of Genetics, Mishima, Shizuoka, Japan; 2) Dept. Microbiology, The Jikei Univ. School of Medicine, Minato-ku, Tokyo, Japan; 3) Dept. of Genetics, Graduate Univ. for Advanced Studies, Shizuoka 411-8540, Japan.

   Sprouty(Spry) and Argos(Aos) are negative regulators of Ras/MAPK pathway triggered by Spitz EGF, acting as a cell autonomous inhibitor or a secreted antagonist of the EGF receptor, respectively. Transcription of both genes is induced by the Ras signal that they inhibit, creating negative feedback loops. Although Spry and Aos are both expressed in all photoreceptor neurons, they exhibit cell-type specific expression levels; While Spry is strongly expressed in R2, R5, R7 photoreceptor neurons throughout their development, Aos expression is initially high in R2/R5 and later is down regulated in those cells, becoming high levels in R3/R4/R1/R6. Loss of spry results in the maintenance of high Aos expression in R2/R5, whereas expression of Spry is largely unaffected by the loss of aos. These data suggest that Spry represses Aos through down-regulating Ras activity. We show that cell type specificity of Spry expression is achieved by the nuclear receptor Seven-up (Svp). Svp is specifically expressed in R3, R4, R1, R6 and represses spry transcription in these cells. Down regulation of Spry may, in turn, contribute to positive regulation of Aos expression in those cells. Thus, Svp functions as a key intrinsic factor that modulates the cell type specificity of the negative regulators, and promotes Aos expression as an induction-off signal. Such cell type specificity of negative regulators is likely to have an important role in ensuring that the induction by a secreted signal generates a constant outcome.