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Of R7 Photoreceptor Cells Proc. Nati. Acad. Sci. USA Vol. 89, pp. 5271-5275, June 1992 Genetics Neuronal development in the Drosophila retina: The sextra gene defines an inhibitory component in the developmental pathway of R7 photoreceptor cells (eye development/sevenless) RONALD ROGGE, Ross CAGAN, ARINDAM MAJUMDAR, TOM DULANEY, AND UTPAL BANERJEE* Department of Biology and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90024 Communicated by Seymour Benzer, March 9, 1992 ABSTRACT Mutations in a gene called sextra (sxt) have R7 cells develop when one copy of boss or of Drasi is been isolated. Loss of one copy of sxt promotes R7 photore- eliminated. ceptor cell development in a genetically sensitized background, In this paper we characterize a gene called sextra (sxt), while loss of both copies results in precursors of non-neuronal which also affects the development of R7 cells. However, cone cells transforming into R7 cells. The requirement for sxt unlike sev+, boss+, Sos+, and Drasl+, which promote the function is cell-autonomous. The transformation of cone-cell development of R7 cells, the wild-type function of sxt in the precursors into R7 cells occurs independently of the sevenless eye is to repress R7 fate. signal. However, the R7 precursor becomes neuronal in an sxt/sxt mutant only in a wild-type sevenless background. The MATERIALS AND METHODS genetic analysis of sxt suggests that it plays an inhibitory role, preventing cone cells from becoming neuronal. Additionally, Genetic Analysis. The sxtBJ6] allele was isolated in a P-el- sxt functions in R7 precursors, but the sevenless sial is ement mutagenesis scheme essentially following Bier et al. essential for specification of this fate, since oss of sextra alone (18), except that a P(ry+) element was used. is unable to impart a neural fate to this cell. For mosaic analysis, females carrying a P[w+] insertion at 78C/D were mated to either sxtlu6I/sxtBJ6' or sxtRI6I,bossl/ Characterization ofa set ofgenes controlling R7 development sxtMu6l,bossl males. Progeny from these crosses were irra- has provided much insight into the process of induction and diated with -y-rays (1200 rads; 1 rad = 0.01 Gy) between 24 signal transduction (1-4). Genetic and molecular analysis of and 48 hr of development. Mosaic eyes were generated at a sevenless (sev) (5-8) and bride of sevenless (boss) (9, 10) has frequency of -0.01. demonstrated that R8 induces a neighboring cell to take on Histology. Preparation ofsamples for transmission electron the R7 fate (9). In boss or sev mutants, R7 cells are missing microscopy (TEM) was essentially as described (19), except within the eye. While the boss protein, a membrane-bound that uranyl acetate staining en bloc was omitted. The sections ligand, is required in the inducing R8 cell for normal R7 were stained for 30 min with uranyl acetate and 10 min with development (11), the sev gene encodes a tyrosine kinase lead citrate and were analyzed on a Phillips 300 electron receptor required in the R7 precursor for it to assume an R7 microscope operating at 60 kV. For light-level microscopy, fate (12, 13). The boss protein has been shown to bind directly the fixation conditions were modified as described (9). To to the sevenless a facilitate scoring of pigment granules, flies were exposed to protein (11), initiating molecular cascade bright light for 10 min before dissection. Cobalt sulfide that causes development of the R7 neuron. staining was done as described (4). Recently, two more genes, Son of sevenless (Sos) and Immunohistochemistry. Adult heads were dissected into Drasi, have been shown to participate in this signal- halves and fixed for 1 hr in 0.8% glutaraldehyde in phosphate- transduction pathway (14-16). Both gain- and loss-of- buffered saline. The retinas were transferred to fresh fixative, function mutations in Sos affect the development ofR7 cells. dissected out of the surrounding cuticle, allowed to fix for Sos functions downstream of sevenless and the Drosophila another 30 min, stained with antibodies (8), and embedded for epidermal growth factor receptor and encodes the Drosophila sectioning (9). Eye imaginal discs were stained with mono- homolog of CDC25 of Saccharomyces cerevisiae. The clonal antibody (mAb) 22C10 and processed for TEM (11). CDC25 product has been shown to be an activator of Ras in yeast (17). It is likely that Sos functions as an activator of Drosophila Rasl. RESULTS A dominant mutation in Sos (called SosJc2) suppresses the Loss of One Copy of sxt Enhances SosJc2. R7 cells develop phenotype of a specific allele (sevE4) of sevenless (14). While in 17% ofthe ommatidia in sevE4/sevE4;SosJc/+ flies (Table sevE4 flies lack all R7 cells, in sevF-/sevE4;SosJc2/+ flies, R7 1). This double mutant serves as a starting point for identi- cells develop in a small fraction of the ommatidia. The sevE4 fication of other genes involved in R7 development. Loss of product is likely to have residual tyrosine kinase activity, and one wild-type copy of boss or Drasi reduces the suppression the SosJC2 product compensates for the partial loss of this level to 0%. These genes have been shown to function as kinase activity by hyperactivating the downstream molecule positive regulators of the pathway (11, 15, 16). Mutations in Ras (14, 16). This is a sensitized system where the fraction of boss or Drasi are normally recessive; only in this sensitized ommatidia in which R7 develops is critically dependent on system does a 2-fold reduction in their activity have an effect the dosage of other genes in the sevenless pathway. For on R7 development. example, in a sevE4/sevF4;SosJc2/+ mutant background, no Mutations in sxt enhance the sevE4/sevE4;SoSJC2/+ phe- notype. Loss ofa single copy ofsxt causes R7 cells to develop The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviation: mAb, monoclonal antibody. in accordance with 18 U.S.C. §1734 solely to indicate this fact. *To whom reprint requests should be addressed. 5271 Downloaded by guest on October 1, 2021 5272 Genetics: Rogge et A Proc. Natl. Acad. Sci. USA 89 (1992) Table 1. Levels of suppression proximally (Fig. 1B). The sxt mutation was made homozy- Ommatidia gous in order to assess its recessive phenotype. Sections of sxt/sxt eyes show that every ommatidium contains multiple % containing No. centrally projecting rhabdomeres (Fig. 1C). Morphologi- Genotype R7 cells scored cally, these are similar to R7 rhabdomeres in that they are sevF-/sevF-4;SosJC2/+ 17 1772 small and project centrally and distally. sevE4/sevF4;sxtBJ6I/+ 0 2259 Serial reconstruction of 61 ommatidia at the electron sevF-/sevF-4;SosJC2/+ ;bossl/+ 0 2337 microscopic level showed that the development of R1-R6 is sevF-/sevF4;SosJC2/+ ;Df(Drasl)/+ 0 2175 not affected in sxt. In 35 of the 61 ommatidia reconstructed, sevF-/sevF4;SosJC2/+ ;sxtBJ61/+ 49 1934 the rhabdomeres ofR1-R6 were found to be displaced, failing Individual ommatidia were scored for the presence of R7 by using to extend the entire length of the ommatidium. However, in the optical technique of pseudopupil (ref. 5 and references therein). no case did an ommatidium contain fewer than six outer The boss I mutation is a null allele. Since a Drasi point mutation was photoreceptor cells. In every ommatidium, a single rhab- not available, Dft3R)by62, a deficiency including this locus, was domere was found to project proximally, in the position ofR8 used. (Fig. 1D). The number of R7-like cells in each ommatidium ranged from 2 to 6, although the majority contained either 3 in 49%o ofthe ommatidia (Table 1), a substantial increase over or 4. The average number was 3.8. the 17% level with two wild-type copies of sxt. In contrast, To ascertain the identity of the extra cells, sxtBJ6' was loss-of-function mutations in all other genes identified in this crossed into a ninaE mutant background. The ninaE mutation assay reduce the number of R7 cells that develop. This causes the rhabdomeres of the outer photoreceptor cells suggests an inhibitory role of sxt in the R7 developmental (R1-R6) to degenerate, leaving the rhabdomeres ofR7 and R8 pathway. intact (Fig. 2A). In sxtBJ6I;ninaE double mutants, the rhab- The ommatidia seen in sevE41sev-4;SosJc21+;sxt/+ flies domeres ofthe extra R cells do not degenerate (Fig. 2B). This never contain more than the one R7 cell, and this cell always implies that the extra cells have the identity ofeither R7 or R8. occupies its wild-type position between R1 and R6. As shown To distinguish between these two possibilities, the type of later, the recessive phenotype ofsxt is to create additional R7 opsin expressed in the extra cells was determined. In Dro- cells-hence the name sextra (for "seven extra"). sophila, two opsins, Rh3 and Rh4, are specific to R7 (20). A Supernumerary R7 Cells Develop in sxt/sxt Eyes. In tan- reporter gene controlled by the Rh4 promoter is expressed in gential sections of wild-type eyes, the rhabdomeres of outer a subset of R7 cells in wild-type eyes (Fig. 2C). In sxtBJ6I a photoreceptors R1-R6 are large and form a trapezoidal similar fraction of the extra central cells express this R7- pattern in each ommatidium. These appear in both proximal specific marker (Fig. 2D). This demonstrates that the central and distal sections (Fig. 1 A and B) because they extend the cells are of the R7 type. entire length ofthe ommatidium. The rhabdomeres ofR7 and * R8 project centrally and are smaller in size. The R7 rhab- A B. ;4oi- domere is found distally (Fig. 1A), whereas R8 extends ,v 4; I.." -.t4' .
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