Repression of Drosophila Photoreceptor C&shte ?’bough ... · Copyright 0 1997 by the Genetics...

Copyright 0 1997 by the Genetics Society of America

Repression of Drosophila Photoreceptor C&shte ?’bough Cooperative Action of Two Transcriptional Repressors Yan and Tramtrack

Zhi-Gun Michael Fetchkot and Yrng Li* *Department of Biology and +Department of Biochemistry and Molecular Biology,

The Pennsylvania State University, University Park, Pennsylvania 16802 Manuscript received January 3, 1997

Accepted for publication July 21, 1997

ABSTRACT The Drosophila yan gene encodes an E twenty-six (ETS) domain nuclear protein with a transcription

repressor activity that can be downregulated through phosphorylation by mitogen-activated protein kinase (MAPK). Before photoreceptor precursor cells commit to a particular cell fate, Yan is requided to maintain them in an undifferentiated state. We report here identification of tramtrack ( t t k ) mutatiqns that act as dominant enhancers of yan. We show that ttk synergistically interacts with yan to inhibit the R7 photoreceptor cell fate. Since ttk products are nuclear proteins with zinc-finger DNA-binding modifs, yan and ttk represent two nuclear regulators essential for the control of cellular competence for neural differentiation. Reduction of either yan or ttk activity suppresses eye phenotypes of the kinase suwasor of rm (ksr) gene mutation, which is consistent with the involvement of yan and ttk in the Ras/MAPK pathway.

I NHIBITORY action of nuclear proteins on gene expression provides an important mechanism for bal- ancing inductive signaling that is mediated by proteins such as receptor tyrosine kinase (RTK). The R7 photoreceptor cell development in the Drosophila eye re- quires two such RTKs, the Drosophila Epidermal Growth Factor Receptor (DER) and the Sevenless (Sev) protein (reviewed by ZIPURSKY and RUBIN 1994; WAS SARMAN et al. 1995; FREEMAN 1997). In the R7 precursor cells, Sevenless (Sev) RTK is activated by binding to its ligand, Bride of Sevenless (Boss). This inductive signal is transmitted through Downstream of receptor kinase (Drk) , Son of sevenless (Sos) , Rasl, Raf and Dsorl, which eventually activates the mitogen-activated protein kinase (MAPK) that is encoded by the rolled (rl) gene. The MAF’K in turn activates an E twenty-six (ETS) DNA- binding domain protein Pointed (Pnt) through phosphorylation (reviewed by DICKSON 1995). As Drosophila Jun (D-Jun) protein is capable to mediate Ras-dependent signaling (BOHMANN et al. 1994), D-Jun may partic- ipate in such regulation by acting together with Pnt (TREIER et al. 1995). Additional nuclear factors include smen in ubsentia (sina), phyllopod (phyl) and pospero (pos) (CARTHEW and RUBIN 1990; CHANG et al. 1995; DICKSON et al. 1995; KAUFFMAN et al. 1996). The sina gene encodes an essential nuclear factor that may coop erate with Phyl to specify the R7 cell fate (UUFFMAN et al. 1996).

Two nuclear repressors, Yan and Tramtrack (Ttk) , in the Ras/MAPK pathway have been studied. A role of

CorrespOnding outhm: Zhi-Chun Lai, Department of Biology, 208 Mueller Laboratory, The Pennsylvania State University, University Park, PA 16802. E-mail: [email protected]

Genetics 147: 1131-1137 (November, 1997)

yan in repressing photoreceptor cell fate in the developing eye was revealed through analyzinlg the ectopic R7 cell phenotype of hypomorphic mutations in the yan gene (LAI and RUBIN 1992; TEI et d. 1992). yan encodes an ETS DNA-binding domain protein that acts as a transcriptional repressor (LAI and RUBIN 1992; TEI et al. 1992; O’NEILL et al. 1994). While Yan activity can be inhibited through phosphorylation @RUNNER et al. 1994; O’NEILL et al. 1994), Yan becomes constitutively active when it can no longer be phosphorylated by MAPK (REBAY and RUBIN 1995). Interestingly, yan has an inhibitory role on cell proliferation as well; when yan activity is completely abolished, mutant cells over- proliferate and eventually die (ROGGE et al. 1995). Thus, yan is a negative regulator in both cell proliferation and differentiation during normal development.

The ttk gene was initially identified as a repressor of segmentation gene expression (HARRISON and TRAVERS 1990; BROWN et al. 1991; READ et al. 1992; BROWN and Wu 1993). ttk encodes two proteins, Ttk69 and Ttk88, through differential splicing of its transcript, such that Ttk69 and Ttk88 share the amino-terminal portion but differ in the carboxyl fragment where the CysrHisp zinc- fingers reside (READ and MANLEY 1992). Overex- pression of t tk69 repressed segmentation gene expression, resulting in embryonic lethal, whereas t tk88 exhib ited no detectable effect (READ et al. 1992; BROWN and WU 1993), In the developing embryonic PNS, both t tk69 and t tk88 are required to specify cell fate of the daughter cells of sensory organ precursors (SOP) (Guo et al. 1995, 1996). As in the case of yan mutations, some ttk mutations result in ectopic R7 cell development (LAI et al. 1996), suggesting that ttk is a negative regulator of photoreceptor cell development. The ectopic R7 cell

1132 Z-C. h i , M. Fetchko and Y. Li

FIGURE 1. - t tk mutations dominantly enhance extra R7 cell phenotype of yan” homozygotes. Scan- ning electron microscopy (A and B) and apical tangential sections (C and D) of Droso hila adult eyes from yan P /yanP (A and C ) and yun”/ynn”; t tk55.3/+ (B and D). External surface of the eye in B is rougher than that in A. This effect is because more ommatidia (75%, n = 580) in the yanP/yan”; ttk55.3/+ fly con- tain ectopic R7 cells as shown in D, comparing to the yanP/yanP (20%, n = 500) fly as shown in C. Cells with a large rhabdomere are outer photorecep tor R1-R6; cells with a small and centrally located rhabdomere are inner photoreceptor R7. R8 photoreceptor cell is located at the basal level and cannot be observed in apical sections. Ommatidia with ectopic R7 cells in yan” mutant eyes are indicated with arrowheads in C.

phenotype was probably caused by the loss of ttk88, since this phenotype was also observed in a ttk88specific mutation, ttk’ (XIONG and MONTELL 1993). However, the role of ttk69 in the eye development has not been clearly clarified due to lack of ttk69specific mutations.

It is unclear whether yan acts alone to repress cell fate, or yan cooperates with other negative regulators in the Drosophila eye development. To address this issue, we have carried out a genetic modifier screen to identify dominant enhancers ofyan [E(yan)] mutations. In this screen, we have identified seven E(yan) mutations that are allelic to ttk. We show here that yan and ttk synergistically interact in an inhibitory signaling pathway that is critical for neural cell fate determination. Both yan and ttk mutations dominantly suppress eye phenotypes of krmutants, indicating that both are involved in the Ras/MAPK pathway, although their mechanisms of action to inhibit cell fate might be different.

MATERIALS AND METHODS

Fly strains: Fly cultures and crosses were carried out under standard conditions (ASHBURNER 1989). yan mutations used in this study were yanX“fn, yan’, yanPzd, and yad’. The yanm’”

mutation was caused by a small internal deletion that trun- cates the yan open reading frame (OW) (I. REBAY, F. WM and G. M. RUBIN, personal communication). yan’ is a strong loss function mutation (LA and RUBIN 1992). yanrZd is a genetic null allele (ROGGE et al. 1995). yad’ has the 22C2-22E1 polytene chromosomal region deleted (G. MARDON, T. LA- VERN and G. M. RUBIN, personal communication). Since the yan gene is located at 22D1-2, it is completely removed in this deficiency. ttk mutations used in this study include the following: ttk’ and Ilk”” (XIONG and MONTELL 1993), ttk””,

, ttp’ and t t p 4 (LAI el al. 1996), and seven EMSin- duced ttk mutations ( X . LAI, unpublished data). ks#r5’x is a viable hypomorphic allele of the kinase supprRFssor of ras (ksr) gene (THERRIEN et al. 1995). ks#F’4x ttk- recombinant chromo- some was generated by recombination.

Clonal analysis of the yunXE’’ mutation: w; yanm”” P[7y+, hsneo, FRT]4OA/CyO flies were constructed, and males were crossed to w, hsFIPI; P[mini-w+, hs-M] P[ry+, hsneo, FRTI4OA female flies to make yanx””x clones in progeny with w, hsIXPl/ v, P[mini-w+, hs-M] P[7y+, hsneo, F R T ] ~ O A / ~ U ~ ~ “ ~ P[7y+, hsneo, FRTI4OA genotype. The first instar larvae were heat- treated at 38” for 1 hr, then allowed to develop at 25’ until eclosed (Xu and RUBIN 1993). Flies with mutant clones were identified by visual inspection of the white gene expression.

Histology: Scanning electron microscopy (SEM) and adult eye section were performed as described (LA et al. 1996). Plastic sections were analyzed using a Zeiss Axioplan com- pound light microscope.

t tyMi3fl

Cell Fate Control by yan and ttk 1133

FIGURE 2.-yanx"'* synergistically interacts with ttk mutations. Apical tangential sections of Drosophila adult eyes with genotypes as follows: (A) yanx""/+; +/+, (B) yanJ2/+; +/+, ( C ) +/+; t t k55 .3 /+ , (D) +/ +; t t p 4 / + , (E) yan,yE'8/+; t t k55 .3 /+ , (F) yanxE"/+;

t t k55 .3 / +, (H) y a d 2 / +; tt#'/ +. Statistical analysis of the results was presented in Table 1. Arrowheads in- dicate occasionally developed ectopic R7 cells in yan"~"*/+ (A) and yad2/+;

t t k a 4 / + , (G) y a ? P / + ;

ttk55,3/ + (G) .

RESULTS as other EMS and P alleles of ttk (Figure 2F). Thus,

Reduction of ttk activity promotes ectopic R7 cell development in the yan mutant eye: We used the yan" mutation to examine genetic interactions between yan and ttk. ynn" mutant eyes were mildly rough (Figure lA), only 20% of ommatidia contained extra R7 cells (Figure 1C). Twofold reduction of the ttk gene activity resulted in the formation of much rougher eyes (Figure 1B) and up to 75% of ommatidia contained extra R7 cells (Figure 1D). Thus, yan and ttk may interact to inhibit the R7 cell fate during normal development.

Synergistic interaction between yap'" and ttk mutations: The dominant enhancement of yan' eye phenotype by ttk mutations strongly suggested a synergistic interaction between these two genes. To substantiate this idea, we have utilized the yanX':'' mutation (KARIM et al. 1996), which is homozygous embryonic lethal. In

tidia carried extra R7 cells (Figure 2A and Table 1 ) . Thirteen ttk mutations, which include seven EMS alleles, three Palleles and three deficiencies, were individ- ually tested in a double heterozygous combination with yanxE'*. Twofold reduction of ttk activity effectively pro- moted formation of ectopic R7 cells (Figure 2, E and F and Table 1 ) . On average, two R7 cells developed in each ommatidium with 70-78% of ommatidia carrying supernumerary R7 cells, whereas only one R7 cell per ommatidium was formed in wild type and in most ommatidia of yanM':'' heterozygotes (Table 1 ) . As a control, ttk mutant heterozygotes were shown to be completely normal (Figure 2, C and D and Table 1) . Among the ttk mutations tested, ttp" represents a chromosomal deficiency that completely deletes the ttk locus, and thus is a t t k null allele (I" et al. 1996). ttp' behaved similarly

Yanxfi:" heterozygotes, a very small number of omma-

yanx","s does not require a specific ttk mutant allele to exert i t s effect on promoting ectopic R7 formation.

To test the idea that yan""" might encode a unique gene product, which is responsible for the dominant negative phenotype that can be further enhanced by reduction of ttk activity, we used several loss-of-function alleles of yan in the double heterozygote assay. Among them was a deficiency y a d 2 in which yan has been completely removed; ommatidia in y a d 2 heterozygotes are completely normal (Figure 2B and Table 1 ) . All 13 ttk

TABLE 1

Genetic interactions between yan and ttk

. . ,

No. of

Genotype ommatidium scored No. of R7 cells/ ommatidia

1. yanX'"*/+; +/+ 1.03 686 3. +/+; ttk55.3/+ 1 .oo 500

5. yan.y"'x/+; ttk55.3/+ 1.90 403 6. yanm..:"8/ +; t t kb4 /+ 2.03 577 7. yanXE'*/ +; ttk'/ + 1.29 520 8. yanJ2/+; ttk55.3/+ 1.01 75 1 9. yanJ2/+; t P 4 / + 1.02 475

10. yanJ2/+; t tk' /+ 1 .oo 885

2. yanJ2/+; +/+ 1 .oo 85 1 4. +I+; t t P 4 / + 1 .oo 840

yan and ttk mutations are described in MATERIALS AND METH- ODS. Adult fly heads were fixed and tangentially sectioned. Ommatidia with ectopic R7 cells were scored. In double heterozygote combinations of yan"""* with all other ttk mutations (5-7), ectopic R7 cells developed in most ommatidia. How- ever, yan12 did not exhibit this effect (8-10). yan' and yan'2d alleles also have little effect on promoting ectopic R7 cell development in this assay (results not shown).

1134 Z-C. Lai, M. Fetchko and Y. Li

FIGURE 3.-Clonal phenotypes ofyan.v"'x mutation. Apical tangential sections of clones of yan,w.'x were generated in eye tissues of w, M L P l / w ; P[mini-w+, hs-MI P[T" hsneo, FRT]40A/yanX"'" P[T+, hsneo, FRT]4OA individuals. The clones' areas were defined by the lack of pigmentation due to the white ( w ) gene mutation. Cells with a large rhabdomere are outer photoreceptor R1-R6; cells with a small and centrally located rhabdomere are R7 cells. Notice some ommatidia in the center of the clone carried sausage-shaped rhab domeres that might be caused by aberrant differentiation. The arrow indicates an ommatidium missing the R7 cell, and the arrowhead shows an ommatidium with an extra R7-like cell.

mutations were tested in double heterozygote combinations with yam'' and shown to be much less effective in promoting ectopic R7 cell formation (Figure 2, G and H and Table 1). Similar results were obtained with a strong loss-of-function mutation yan' and a null allele yanrZd (results not shown). Thus, it seems that a new function was gained in the yanm" mutation, in terms of its capacity to interact with ttk mutations.

The ttk gene encodes two zinc-finger DNA-binding proteins, Ttk69 and Ttk88, through differential splicing of the ttk transcript (HARRISON and TRAVE= 1990; READ and MANLEY 1992). XIONC and MONTELL (1993) have shown that tlk' is a ttk88specific mutation. Interestingly, eyes of the yanX'*/+; ttk'/+ flies were moderately rough with 1.3 R7 cells per ommatidium (Table 1). This suggests that Ttk88 does genetically interact with Yan. It is possible that Ttk69 interacts with Yan as well, since complete deletion of ttk69 and ttk88 in ttp' further enhanced yan eye phenotype (2.0 R7 cells/ommatidium, Table 1). However, ttk' may not be a null mutation; the effect exhibited by ttp' may be due to a complete loss of ttk88.

Eye phenotypes of the yanm'* mutation were exam- ined using the FRT-FLP recombination system (Xu and RUBIN 1995). yan"' mutant clones were generated in yanm'* heterozygotes. In regions abutting wild-type t is sues and mutant clones, some ommatidia were found either missing the R7 cell or having an extra R7-like cell (Figure 3). Interestingly, ommatidia in the center of the mutant clones generally contained fewer phot* receptor cells. Morphology of their rhabdomeres was abnormal, suggesting an aberrant differentiation (Fig-

ure 3). Two aspects of yan gene function have been illustrated in previous studies: one is repression of photoreceptor cell fate and the other is inhibition of cell proliferation at an early stage of eye formation. Ectopic photoreceptor cells developed in yan' mutant eyes, suggesting that yan is a repressor of photoreceptor cell fate ( L A and RUBIN 1992). However, residual yan activity in yan' mutants may allow cells to divide normally. Com- plete elimination of yanactivity resulted in cell overprol- iferation in developing eye discs (ROCCE et al. 1995). These cells usually died, thus leaving behind scars in adult retinas. Mutant phenotypes observed in yan-

clones, together with the unique interactions between yanW"* and ttk-, support the notion that yan"'' may not be simply a loss-of-function mutation.

Reduction of yun and ttA gene activity dominantly suppresses the missing R7 cell phenotype of ksr mutation: To determine how yan and ttk act in the Ras/ MAPK pathway, we have tested genetic interactions of yan and ttk with other components in the pathway that include Rml, DraJ Dsorl, and rl ( L A and RUBIN 1992; LA et al. 1996). It is clear that yan is a nuclear target of the Ras/MAPK signaling pathway. Reduction of the yan activity enhances the extra R7 cell phenotype in sev- R U S I ~ ' ~ , sE-raf I"', and sE-rl'*" ( L A and RUBIN 1992; LA et al. 1996), and suppresses the missing R7 cell phenotype in BufHM7 and D.$mlx.'520 ( W M et al. 1996; et al. 1996). This is consistent with biochemical evidence that suggests Yan being a substrate of a MAPK Phos- phorylation of Yan is thought to lead to its inactivation, thus allowing R7 cell fate specification (BRUNNER et al. 1994; O'NEILL et al. 1994; REBAY and RUBIN 1995). Re- cently, another protein kinase encoded by the itsrgene has been identified, and it may act to modulate the signaling output of the Rasl/WKpathway (THERRIEN et al. 1995, 1996). The itsrgene is essential for photoreceptor cell development; loss of the itsrfunction results in the failure of photoreceptor cell formation. When yan activity was reduced, it effectively suppressed the rough eye phenotype of hypomorphic k d n 4 * mutants (compare Figure 4B with 4A). Whereas only 8.4% of M ( F 5 4 R ommatidia cany the normal complement of photoreceptor cells (Figure 4D), up to 99% of ommatidia in yanm:'*/+; k s ~ ~ ~ ' ~ ~ ~ / ~ ~ ~ ~ flies were normal (Figure 4E). ttk mutations were also effective suppres- sors, as eyes of k d F 5 ' * t t k - /kdS5 '* + were normal in their external morphology (compare Figure 4C with 4A) and 65-75% of their ommatidia were wild type (Figure 4F). Thus, both yan and ttk are downstream effectors of the Ras/MAPK pathway.

X E I R

DISCUSSION

yan is a nuclear component in the Sevenless signaling pathway. As yan functions to maintain precursor cells in an undifferentiated state, reduction of yan activity facilitates signaling processes mediated by the Rasl/


?

FIGURE 4.-Genetic interactions between yan, ttk, and br mutations. Genetic interactions between ksr and yan, or ttk were revealed by scanning electron microsco (A-C) and tan entia1 sections (D-F) of the Drosophila eyes. (A and D) k . d S 5 ' * /

k .d '548 were completely suppressed by yan (B and E) and strongly suppressed by t tk (C and F). In k.dF548 mutants, 8.4% (n = 486) ommatidia were wild type. However, y~n.'"'~/+; ksrxs548 flies contained 99% (n = 509) wild- e ommatidia and ttk'"O.'/k~#''~'~ + flies carried 75% (n = 1120) normal-looking ommatidia. Another ttk mutation, ttk'" ', also rescued ksr mutant eye phenotypes (results not shown).

w \ ' 5 4 8 . (B and E) yanx/';18/+; w $ 5 4 8 / & y $ 4 8 . (C and F) k.v's548 ttk'W'.'/ksP"4X +. Rough eye and missin R7 cell phenotypes of

T

MAPK cascade. Genetic analysis of ttk interactions with components of the Rasl/MAPK cascade supports the notion that mechanism of ttk action is different from that of yan (LAI et al. 1996). To further define how ttk might be involved in inhibiting the R7 cell fate, we tested its genetic interaction with the br gene, which encodes a po!lypeptide most closely related to raf ser- ine/threonine protein kinase and may act to modulate

signal output of the Ras/MAPK cascade (THERRIEN et al. 1995,1996). We have shown that reduction of either yan or ttk activity effectively suppresses br mutant eye phenotypes, which further indicates that yan and ttk are involved in the Ras/MAPK signaling pathway.

We have shown that yan and ttk synergistically interact to repress photoreceptor cell fate. An immediate question is what would be the molecular mechanisms responsible

1136 ZC. Lai, M. Fetchko and Y, Li

for this genetic intextion. Based on the fact that p n acts upstream of sins and ttk acts downstream of sinu (LAI and RUBIN 1992; LAI et al. 199% YWOTO et al. 1996), we expect that interaction between yun and ttk does not occur through direct protein association. No direct physical interaction between Yan and Ttk was observed in a yeast twe hybrid m y (A TANG and G. M. RUBIN, personal communication). A more likely scenario is that yun controls expression of downstream genes that are critical for regdating ttk expression or function. The sinu gene is unlikely a direct target of p n since Rasl signaling does not alter sina expression (R WTHEW, pesonal communication), A strong candidate target gene is fihy!, which was shown to act downstream of yun and upstream of sins, and phyl transcription was elevated through inductive Rasl signaling (CHANG d al. 1995; DICKSON et al. 1995). In y~n"'~ heterozygotes, phyl expression might be upregulated. Reduction of ttk function in a ~ u n ~ ' ~ heterozygote background may Eacilitate ph$ to repress ttk expression or function to a level at which ectopic R7 photoreceptors would develop.

The yanm18 mutation exhibits a weak dominant extra R7 cell phenotype in the eye and this is not due to haploid insufliciency of loss-of-function mutation, because mutations that completely abolish yan activity (such as an"^) do not exhibit any dominant eye phenotypes. Clonal analysis revealed that cells homozygous for yunXE1' behave differently when compared with that of yanezd and yun'. The yanXE" mutation results in abnormal development of ommatidia, which includes aberrant differentiation of photoreceptor cells. In double heterozygote combinations with ttk mutations, JanJ2, a deficiency with complete loss of yan function, was much less effective in promoting ectopic R7 cell development. These results support the notion that yanXEZ8 may encode a unique function. Indeed, molecular analysis of yanXE" revealed that an out-of-frame deletion intro- duced a new stop codon, so that a protein with the amino-terminal polypeptide of 185 amino acids in Yan plus 49 new amino acids could be produced (I. REBAY, F. KARIM and G. M. RUBIN, personal communication), although such truncated Yan protein was not detected on Western blots with Yan antibodies (M. FETCHKO and L C . LAI, unpublished data). It is interesting to note that the amineterminal sequence contains a highly conserved Pointed domain protein motif (KLAMBT 1993), whose function has not been revealed.

We thank R. CARTHEW, F. KARIM, G. MARDON, I. REBAY, A. TANG and G. M. RUBIN for communicating unpublished data. We thank U. BANERJEE, H. CHANG, F. KARIM, G. MARDON, C. MONTELL and G. M. RUBIN for fly strains. We also appreciate A. CLARI(, R. ORDWAY and members of the LAI Laboratory for helpful comments on this manuscript. ZC.L. is a recipient of a March of Dimes Basil O'Connor Starter Scholar Research Award. This work was supported by National Science Foundation grant IBN9511201 to 2-C.L.

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Communicating editor: R. S. HAWLEY

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