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DEAF-1 Function Is Essential for the Early Embryonic Development Of ©2002Wiley-Liss,Inc. genesis33:67–76(2002) ARTICLE DEAF-1FunctionIsEssentialfortheEarlyEmbryonic DevelopmentofDrosophila AlexeyVeraksa,1†JamesKennison,2 andWilliamMcGinnis1* 1DivisionofBiology,UniversityofCalifornia,SanDiego,LaJolla,California 2LaboratoryofMolecularGenetics,NationalInstitutesofHealth,Bethesda,Maryland Received8February2002;Accepted19March2002 Summary:TheDrosophilaproteinDEAF-1isase- coreofaminoacidresiduesinDEAF-1andotherproteins quence-specificDNAbindingproteinthatwasisolated (GrossandMcGinnis,1995).NUDR(nuclearDEAF-1- asaputativecofactoroftheHoxproteinDeformed(Dfd). relatedfactor,alsoknownasSuppressinormDEAF-1)is Inthisstudy,weanalyzetheeffectsoflossorgainof anapparentmammalianorthologofDEAF-1andisthe DEAF-1functiononDrosophiladevelopment.Maternal/ zygoticmutationsofDEAF-1largelyresultinearlyem- onlynon-DrosophilaproteincontainingboththeSAND bryonicarrestpriortotheexpressionofzygoticseg- andthecarboxy-terminalMYNDdomain(Huggenviket mentationgenes,althoughafewembryosdevelopinto al.,1998;LeBoeufetal.,1998;Sugiharaetal.,1998; larvaewithsegmentationdefectsofvariableseverity. Michelsonetal.,1999;Bottomleyetal.,2001).NUDR OverexpressionofDEAF-1proteininembryoscanin- wascharacterizedasanuclearDNAbindingproteinthat ducedefectsinmigration/closureofthedorsalepider- alsopreferentiallybindsDNAsitescontainingTTCGmo- mis,andoverexpressioninadultprimordiacanstrongly tifs,withapreferenceforclusteredTTCGsequences. disruptthedevelopmentofeyeorwing.TheDEAF-1 ExperimentsonNUDRsuggestthatitisrequiredto proteinassociateswithmanydiscretesitesonpolytene chromosomes,suggestingthatDEAF-1isarathergen- activatetheproenkephalinpromoter(Huggenviketal., eralregulatorofgeneexpression. genesis33:67–76, 1998),butinamannerthatdoesnotinvolveDNAbind- 2002.©2002Wiley-Liss,Inc. ing.Incontrast,NUDRprotein,aswellasNUDRDNA bindingsites,arerequiredfortherepressionofthe Keywords:Drosophila;DEAF-1;Deformed;Hox;segmen- hnRNPA2/B1promoterintissueculturecells(Michel- tation sonetal.,1999). UnpairedcopiesoftheSANDandMYNDdomainsare alsofoundinotherproteins.AdivergentSANDdomain INTRODUCTION ispresentintheSP100familyofproteins,whichare localizedtosubnuclearstructures(PMLbodies),andare TheDEAF-1proteinwasidentifiedasproteinthatbound thoughttoplayaroleintheetiologyofacutepromyelo- toDNAsitescontainingTTCGnucleotidesinanautoreg- cyticleukemia(reviewedinZhongetal.,2000).Differ- ulatoryenhancerthatistranscriptionallyactivatedbythe entSP100isoformsassociatewithchromatincompo- DrosophilaHoxproteinDeformed(Dfd)(Grossand nents,andwhenboundtoapromoter,behaveas McGinnis,1995;Lietal.,1999b;Zengetal.,1994). transcriptionalactivatorsorrepressors(reviewedinBot- Initially,DEAF-1wasproposedtobeacofactorthat tomleyetal.,2001).Otherwell-studiedSANDdomain assistedinthemaxillary-specificactivationofthissmall proteinsincludeGMEB-1andGMEB-2(glucocorticoid Dfdresponseelement(GrossandMcGinnis,1995).How- modulatoryelementbindingfactors;Oshimaetal.,1995; ever,furthermutagenesisofthemoduleEDfdresponse The´riaultetal.,1999;Zengetal.,1998).Theirhetero- element,aswellasaDfdresponseelementfromthe oligomericcomplexwasshowntobindvariablyspaced Drosophila1.28gene,hasindicatedthattheTTCG PuCGPymotifs.Incelltransfectionassays,GMEB-1and DEAF-1bindingmotifsarenotrequiredfortheactivation ofeitherelement(Lietal.,1999;Pedersonetal.,2000). Grantsponsor:NationalInstituteofChildHealth/HumanDevelopment. InDrosophilaembryos,DEAF-1proteinisubiqui- † Currentaddress:MGHCancerCenter,HarvardMedicalSchool,Charles- touslyexpressedandappearstobeconstitutivelylocal- town,MA02129. izedinnuclei.TheDEAF-1proteincontainstwocon- *Correspondenceto:WilliamMcGinnis,DivisionofBiology,0349,Uni- serveddomains,SANDandMYND,whicharepresentin versityofCalifornia,SanDiego,9500GilmanDr.,LaJolla,CA92093-0349. E-mail:[email protected] severaltranscriptionfactors.TheSANDdomain(for Publishedonline00Month2002in SP100,AIRE-1,NucP41/75andDEAF-1;Gibsonetal., WileyInterScience(www.interscience.wiley.com) 1998)wasoriginallynamed“KDWK”afteraconserved DOI:10.1002/gene.10090 68 VERAKSA ET AL. GMEB-2 have been shown to function as transcriptional are frequent in nearby chromosomal regions (Tower et activators, repressors, or modulators (Christensen et al., al., 1993), we mobilized the transposition of the P ele- 1999; Jimenez-Lara et al., 2000; Kaul et al., 2000). The ment P{lacW}l(3)L0189, which is inserted approxi- three-dimensional structure of a SAND domain has been mately 32 kb from the 3Ј end of the DEAF-1 transcription recently determined (Bottomley et al., 2001). The au- unit. In progeny from flies with potential transpositions, thors proposed that the SAND domain represents a novel we used an inverse polymerase chain reaction (PCR) DNA binding module characteristic for chromatin-de- method (modified from Dalby et al. 1995, see Materials pendent transcriptional regulation. and Methods) to screen for insertions or deletions in a The MYND domain (myeloid, Nervy, and DEAF-1) is cloned genomic interval containing DEAF-1 (cosmid present in a large group of proteins that includes RP-8 104C6 and P1 clone DS00027). A map of the genomic (PDCD2), Nervy, and several ESTs and predicted pro- region containing DEAF-1 and adjacent genes is shown teins from Drosophila, mammals, C. elegans, yeast, and in Figure 1a. No simple transpositions into DEAF-1 were plants (Feinstein et al., 1995; Gross and McGinnis, 1995; recovered. However, after screening 2000 lines, we ob- Owens et al., 1991). The MYND domain consists of a tained a deletion, Df(3L)25-21, that removes a genomic cluster of cysteine and histidine residues, arranged with region flanking the left side of the L0189 P element, an invariant spacing to form a potential zinc-binding including the entire DEAF-1 locus (Fig. 1a, black rectan- motif (Gross and McGinnis, 1995). Mutating conserved gle). The absence of DEAF-1 sequences on the cysteine residues in the DEAF-1 MYND domain does not Df(3L)25-21 chromosome was confirmed by Southern abolish DNA binding, which suggests that the MYND blot analysis (data not shown). domain might be involved in protein-protein interactions This region of the third chromosome is also deleted in (Gross and McGinnis, 1995). Indeed, the MYND domain Df(3L)kto2, and a large screen has been done to identify of ETO/MTG8 interacts directly with the N-CoR and EMS-induced lethal complementation groups that map SMRT corepressors (Gelmetti et al., 1998; Lutterbach et within this deficiency (J. Kennison, unpublished results). al., 1998a, 1998b; Wang et al., 1998). Aberrant recruit- Further genetic tests have shown that Df(3L)25-21 and ment of corepressor complexes and inappropriate tran- Df(3L)kto2 both uncover five lethal complementation scriptional repression is believed to be a general mech- groups including tricorner (trc) and kohtalo (kto). To anism of leukemogenesis caused by the t(8;21) determine whether one of these complementation translocations that fuse ETO with the acute myelogenous groups corresponded to DEAF-1, we used P element leukemia 1 (AML1) protein. Recently, ETO was shown to transformation to make transgenic lines containing a be a corepressor recruited by the promyelocytic leuke- genomic rescue construct that included all of the mia zinc finger (PLZF) protein (Melnick et al., 2000). A DEAF-1 transcription unit plus approximately 4 kb on divergent MYND domain present in the adenovirus E1A each side (Fig. 1a, gray rectangle). binding protein BS69 was also shown to interact with Only the k3 and S10B alleles, in the same complemen- N-CoR and mediate transcriptional repression (Masselink tation group, were adult viable in combination with the and Bernards, 2000). The current evidence suggests that DEAF-1 genomic rescue construct. PCR amplification the MYND motif in mammalian proteins constitutes a and sequencing of the DEAF-1 open reading frame from protein-protein interaction domain that functions as a these mutant chromosomes revealed that k3 hasaGto corepressor-recruiting interface. A transition that changes a cysteine codon TGT (amino Despite all of the molecular and biochemical informa- acid 262) to a tyrosine codon TAT. In S10B,aGtoA tion concerning DEAF-1 and related proteins, the lack of transition changes a tryptophan codon TGG (amino acid conventional genetic studies has hampered the under- 400) to a stop codon TGA. No other codon changes standing of this family of transcription factors. In this were detected in the rest of the DEAF-1 open reading study, we have identified and characterized mutations in frame in these mutants. Based on the genetic rescue, the Drosophila DEAF-1 gene. DEAF-1 maternal function complementation results, and identification of mutations is essential for early embryonic development, as most in the open reading frame of DEAF-1, we conclude that maternal mutant embryos arrest before reaching the k3 and S10B are mutant alleles of DEAF-1 (DEAF-1k3 and stage at which the zygotic segmentation genes are acti- DEAF-1S10B). The locations of these mutations in the vated. DEAF-1 protein sequence are shown in Figure 1b. RESULTS Phenotypic Analysis of DEAF-1k3 and DEAF-1S10B Mutants Identification of Mutations in the DEAF-1 Gene The effects on embryos of zygotic loss of DEAF-1 To gain insight into the biological functions of function were assayed by analysis of transheterozygous DEAF-1,wefirst identified mutations in the gene using combinations of DEAF-1k3 and DEAF-1S10B over each (1) local P element transpositions and (2) rescue of other and over Df(3L)25-21. The zygotic DEAF-1 mu- lethality of potential mutants with a genomic rescue tants developed
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