A Comparison of Deformed-Responsive Elements

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A Comparison of Deformed-Responsive Elements Copyright 2000 by the Genetics Society of America Regulation by Homeoproteins: A Comparison of Deformed-Responsive Elements Jeffrey A. Pederson,*,1 James W. LaFollette,* Cornelius Gross,²,2 Alexey Veraksa,² William McGinnis² and James W. Mahaffey* *Department of Genetics, North Carolina State University, Raleigh, North Carolina 27695-7614 and ²Department of Biology, University of California, San Diego, California 92093 Manuscript received March 8, 2000 Accepted for publication June 1, 2000 ABSTRACT Homeotic genes of Drosophila melanogaster encode transcription factors that specify segment identity by activating the appropriate set of target genes required to produce segment-speci®c characteristics. Advances in understanding target gene selection have been hampered by the lack of genes known to be directly regulated by the HOM-C proteins. Here we present evidence that the gene 1.28 is likely to be a direct target of Deformed in the maxillary segment. We identi®ed a 664-bp Deformed Response Element (1.28 DRE) that directs maxillary-speci®c expression of a reporter gene in transgenic embryos. The 1.28 DRE contains in vitro binding sites for Deformed and DEAF-1. The Deformed binding sites do not have the consensus sequence for cooperative binding with the cofactor Extradenticle, and we do not detect coopera- tive binding to these sites, though we cannot rule out an independent role for Extradenticle. Removing the four Deformed binding sites renders the 1.28 DRE inactive in vivo, demonstrating that these sites are necessary for activation of this enhancer element, and supporting the proposition that 1.28 is activated by Deformed. We show that the DEAF-1 binding region is not required for enhancer function. Comparisons of the 1.28 DRE with other known Deformed-responsive enhancers indicate that there are multiple ways to construct Deformed Response Elements. ISTINCT morphological structures exist along the The products of the homeotic genes (homeoproteins) D anterior-posterior axes of animals. In Drosophila function as transcription factors (reviewed by Hayashi melanogaster the homeotic complex (HOM-C) genes are and Scott 1990). They contain a highly conserved 60- integral components of the pathways that ascribe differ- amino-acid DNA-binding domain known as the homeo- ent identities to cells along this axis (reviewed by domain (McGinnis et al. 1984; Scott and Weiner 1984; McGinnis and Krumlauf 1992). The HOM-C has been reviewed by Scott et al. 1989). Homeoproteins are conserved throughout evolution and is found in all ani- thought to specify segmental identity by activating the mals examined (McGinnis and Krumlauf 1992; Krum- appropriate battery of target genes that ultimately produce lauf 1994; Manak and Scott 1994). In Drosophila the segment-speci®c characteristics (reviewed by Andrew and HOM-C genes are found in two complexes: the Bithorax Scott 1992; Botas 1993; Morata 1993). Yet, how this complex and the Antennapedia complex (Lewis 1978; Ben- is achieved remains unknown. For several reasons it is der et al. 1983; Sanchez-Herrero et al. 1985; Akam unclear how the speci®city of target gene selection is 1989; Kaufman et al. 1990; Kessel and Gruss 1990; attained. Different homeoproteins recognize very simi- Lufkin et al. 1992; Ramirez-Solis et al. 1993). The genes lar DNA sequences in vitro and have nearly identical of the Bithorax complex (Ultrabithorax, abdominal A, and binding af®nities (Desplan et al. 1988; Hoey and Abdominal B) specify segment identity in the posterior Levine 1988; Affolter et al. 1990; Florence et al. 1991; thorax and abdominal region. The genes of the Anten- Dessain et al. 1992; Ekker et al. 1994; Walter et al. napedia complex (labial, proboscipedia, Deformed, Sex combs 1994). Further, a single homeoprotein can recognize a reduced, and Antennapedia) specify segmental identity in variety of DNA sequences (though almost all have the the head and anterior thorax. core sequence TAAT). On certain sites with TAAT (or subtle variants of that sequence) an immediately up- stream site, TGAT, leads to cooperative heterodimer Corresponding author: James W. Mahaffey, Department of Genetics, binding of the Hox protein with the Extradenticle (Exd) North Carolina State University, Raleigh, NC 27695-7614. protein (Chan and Mann 1996). This interaction en- E-mail: [email protected] hances the sequence speci®city of Hox DNA binding 1 Present address: Wyeth-Lederle Vaccines and Pediatrics, Sanford, NC 27330. and appears to be required for some Hox proteins to 2 Present address: Center for Neurobiology and Behavior, Columbia function as transcriptional activators (Li et al. 1999b). University, New York 10032. Hox/Exd heterodimer binding sites are found in a sub- Genetics 156: 677±686 (October 2000) 678 J. A. Pederson et al. set of Hox response elements, but it is still unclear SmaI sites of pBS. The resulting construct was excised from whether Exd function is required on all response ele- pBS by digestion with BamHI and HindIII and subcloned into pHSS7, then into pHZ-white. Plasmids were puri®ed using ments or only on some. QIAGEN'S (Valencia, CA) plasmid midi kit. DNA was ethanol To understand HOM-C speci®cation of axial pat- precipitated and resuspended in injection buffer (Spradling terning, it is necessary to identify downstream target and Rubin 1982; Ashburner 1989) at a concentration of 400 genes that are controlled by speci®c homeoproteins. ng/␮l. Drosophila transformation followed the procedure of Identi®cation of similarly regulated target genes would Robertson et al. (1988). Numbers of independent ¯y lines for each construct are as follows: 1.28 DRE,8;1.28 mut1-4,4; allow comparisons of the regulating enhancers, and 1.28 DRE Deformed binding region, 10; 1.28 DEAF-1 binding this could lead to the identi®cation of important cues region, 3; chimera 1,5;chimera 2,3. in target gene regulation. There have been several DNase I footprint assays: Deformed protein was produced attempts to systematically identify downstream target in Escherichia coli and puri®ed according to Dessain et al. genes (Gould et al. 1990; Gould and White 1992; (1992). DNase I footprinting experiments were carried out as described in Heberlein et al. (1985). DEAF-1 protein puri®- Wagner-Bernholz et al. 1991; Graba et al. 1992; cation and footprint reactions followed the protocol of Gross Mahaffey et al. 1993; Feinstein et al. 1995; Mastick and McGinnis (1996). et al. 1995; Botas and Auwers 1996). Unfortunately, Site-directed mutagenesis: Site-directed mutagenesis fol- the regulatory regions of only a few target genes have lowed the protocol of Kunkel et al. (1987). The 1.28 DRE was been characterized in suf®cient detail to identify ho- subcloned into pBS as described above. The pBS clone was transformed into CJ236 and selected on ampicillin (Amp) and meotic response elements. These include the regulatory chloramphenicol (CAM). Cells from this culture were patched regions of teashirt (tsh), decapentaplegic (dpp), and De- onto LB plates containing 50 ␮g/ml Amp and 10 ␮g/ml CAM formed. tsh controls head vs. trunk development, and and were allowed to grow for 5 hr. A small loop of cells was high levels of tsh expression in the thoracic epidermis used to inoculate 10 ml 2ϫ YT containing 50 ␮g/mlAmp,10 require Antennapedia function (Fasano et al. 1991; ␮g/ml CAM, and 0.25 ␮g/ml uridine. After 40 min at 37Њ, the helper phage M13K07 was added. After an additional 30 McCormick et al. 1995). Transcriptional regulation of min, kanamycin was added to a ®nal concentration of 70 ␮g/ tsh by Antennapedia is probably direct and involves se- ml and the culture was allowed to grow overnight at 37Њ. Phage quences in addition to the homeoprotein binding sites. were isolated by precipitation with 4% PEG/0.5 m NaCl. The dpp is a member of the transforming growth factor phage were resuspended in 100 ␮l TE, phenol-extracted, and (TGF)-␤ family of proteins and has been shown to be precipitated. A 10-fold molar excess of mutagenizing primer was added to template DNA. Primer extension reactions in- directly regulated by multiple homeoproteins in the em- cluded 5 units of Klenow, 0.5 mm dNTPs, and 800 units of bryonic midgut (Padgett et al. 1987, 1993; Capovilla T4 ligase. The primer extension reaction was transformed into et al. 1994; Manak et al. 1994; Sun et al. 1995). The SURE cells (Stratagene, La Jolla, CA). homeotic gene Deformed is itself a target of HOM-C re- In situ hybridization: Embryos for whole-mount in situ local- gulation through autoregulatory activation during em- ization of 1.28 or ␤-g␣l transcripts were dechorionated and bryonic development, and several autoregulatory ele- ®xed following the procedure of Tautz and Pfei¯e (1989). In situ hybridization analysis used ribonucleotide probes gen- ments have been identi®ed that function as Deformed- erated with an RNA transcription kit (Stratagene) and DIG- responsive maxillary enhancers (Regulski et al. 1991; 11-UTP (Boehringer Mannheim, Indianapolis). Hybridization Zeng et al. 1994; Gross and McGinnis 1996). In addi- was carried out using modi®cations to the method of Tautz tion, two potential targets of Deformed have been iden- and Pfei¯e (1989). Anti-DIG-AP (Boehringer Mannheim) ti®ed, Distal-less (O'Hara et al. 1993) and 1.28 (Mahaf- was used to detect hybridization. Chimeric enhancer construction: The 120-bp module E ele- fey et al. 1993), respectively. ment was subcloned into the HindIII site of pBS and oriented In this article, we describe results of experiments indi- so the Deformed binding region could be ampli®ed using cating that the Drosophila 1.28 gene is likely to be a the forward primer and the DEAF-1 binding region could be direct target of the Deformed homeoprotein. This ampli®ed using the reverse primer. Primer 120 Deformed was allows us to compare activation of 1.28 with autoregula- designed to amplify the Deformed binding region of module E and has the sequence 5Ј-GGAAGCTTCGCCAGTCGGT tion of Deformed, where a molecular basis for De- TGG-3Ј.
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