Identification of a retinoic acid response element upstream of the murine Hox-4.2 gene.

Mol Cell Biol. 1993 January; 13(1): 257–265.

PMCID: PMC358905

H Pöpperl and M S Featherstone

McGill Cancer Centre, Montréal, Québec, Canada.

This article has been cited by other articles in PMC.

Abstract

Hox genes play an important role in the process of vertebrate pattern formation, and their expression is intricately regulated both temporally and spatially. All-trans-retinoic acid (RA), a physiologically active metabolite of vitamin A, affects the expression of a large number of Hox genes in vitro and in vivo. However, the regulatory mechanisms underlying the RA response of these genes have not been extensively studied, and no response element for RA receptors (RARs) has been characterized in a Hox regulatory region. The expression of murine Hox-4.2 and its human homolog, HOX4B, is increased in embryonal carcinoma (EC) cell lines upon RA treatment (M. S. Featherstone, A. Baron, S. J. Gaunt, M.-G. Mattei, and D. Duboule, Proc. Natl. Acad. Sci. USA 85:4760-4764, 1988; A. Simeone, D. Acampora, V. Nigro, A. Faiella, M. D'Esposito, A. Stornaiuolo, F. Mavilio, and E. Boncinelli, Mech. Dev. 33:215-228, 1991). Using transient expression assays, we showed that luciferase reporter gene constructs carrying genomic sequences located upstream of Hox-4.2 responded to RA in murine P19 EC cells. A 402-bp NcoI fragment was necessary for the RA responsiveness of reporter constructs. This fragment contained a regulatory element, 5'-AGGTGA(N)5AGGTCA-3', that closely resembles the consensus sequence for an RA response element. The Hox-4.2 RA response element was critical for the RA induction and specifically bound RARs. In addition, the response to RA could be inhibited by expressing a dominant negative form of RAR alpha in transfected P19 EC cells. These results suggested that Hox-4.2 is a target for RAR-mediated regulation by RA.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Image
on p.262

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

Langston, AW; Gudas, LJ. Identification of a retinoic acid responsive enhancer 3' of the murine homeobox gene Hox-1.6. Mech Dev. 1992 Sep;38(3):217–227. [PubMed]
Arcioni, L; Simeone, A; Guazzi, S; Zappavigna, V; Boncinelli, E; Mavilio, F. The upstream region of the human homeobox gene HOX3D is a target for regulation by retinoic acid and HOX homeoproteins. EMBO J. 1992 Jan;11(1):265–277. [PubMed]
Chisaka, O; Capecchi, MR. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature. 1991 Apr 11;350(6318):473–479. [PubMed]
Chisaka, O; Musci, TS; Capecchi, MR. Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature. 1992 Feb 6;355(6360):516–520. [PubMed]
Cianetti, L; Di Cristofaro, A; Zappavigna, V; Bottero, L; Boccoli, G; Testa, U; Russo, G; Boncinelli, E; Peschle, C. Molecular mechanisms underlying the expression of the human HOX-5.1 gene. Nucleic Acids Res. 1990 Aug 11;18(15):4361–4368. [PubMed]
Colberg-Poley, AM; Püschel, AW; Dony, C; Voss, SD; Gruss, P. Post-transcriptional regulation of a murine homeobox gene transcript in F9 embryonal carcinoma cells. Differentiation. 1987;35(3):206–211. [PubMed]
Courtois, G; Baumhueter, S; Crabtree, GR. Purified hepatocyte nuclear factor 1 interacts with a family of hepatocyte-specific promoters. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7937–7941. [PubMed]
Dencker, L; Gustafson, AL; Annerwall, E; Busch, C; Eriksson, U. Retinoid-binding proteins in craniofacial development. J Craniofac Genet Dev Biol. 1991 11(4):303–314.Oct–Dec; [PubMed]
Deschamps, J; de Laaf, R; Joosen, L; Meijlink, F; Destrée, O. Abundant expression of homeobox genes in mouse embryonal carcinoma cells correlates with chemically induced differentiation. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1304–1308. [PubMed]
De Simone, V; De Magistris, L; Lazzaro, D; Gerstner, J; Monaci, P; Nicosia, A; Cortese, R. LFB3, a heterodimer-forming homeoprotein of the LFB1 family, is expressed in specialized epithelia. EMBO J. 1991 Jun;10(6):1435–1443. [PubMed]
Dollé, P; Izpisúa-Belmonte, JC; Falkenstein, H; Renucci, A; Duboule, D. Coordinate expression of the murine Hox-5 complex homoeobox-containing genes during limb pattern formation. Nature. 1989 Dec 14;342(6251):767–772. [PubMed]
Dollé, P; Ruberte, E; Kastner, P; Petkovich, M; Stoner, CM; Gudas, LJ; Chambon, P. Differential expression of genes encoding alpha, beta and gamma retinoic acid receptors and CRABP in the developing limbs of the mouse. Nature. 1989 Dec 7;342(6250):702–705. [PubMed]
Dollé, P; Ruberte, E; Leroy, P; Morriss-Kay, G; Chambon, P. Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis. Development. 1990 Dec;110(4):1133–1151. [PubMed]
Featherstone, MS; Baron, A; Gaunt, SJ; Mattei, MG; Duboule, D. Hox-5.1 defines a homeobox-containing gene locus on mouse chromosome 2. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4760–4764. [PubMed]
Forman, BM; Samuels, HH. Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model. Mol Endocrinol. 1990 Sep;4(9):1293–1301. [PubMed]
Galliot, B; Dollé, P; Vigneron, M; Featherstone, MS; Baron, A; Duboule, D. The mouse Hox-1.4 gene: primary structure, evidence for promoter activity and expression during development. Development. 1989 Oct;107(2):343–359. [PubMed]
Gaunt, SJ; Krumlauf, R; Duboule, D. Mouse homeo-genes within a subfamily, Hox-1.4, -2.6 and -5.1, display similar anteroposterior domains of expression in the embryo, but show stage- and tissue-dependent differences in their regulation. Development. 1989 Sep;107(1):131–141. [PubMed]
Glass, CK; Devary, OV; Rosenfeld, MG. Multiple cell type-specific proteins differentially regulate target sequence recognition by the alpha retinoic acid receptor. Cell. 1990 Nov 16;63(4):729–738. [PubMed]
Glass, CK; DiRenzo, J; Kurokawa, R; Han, ZH. Regulation of gene expression by retinoic acid receptors. DNA Cell Biol. 1991 Nov;10(9):623–638. [PubMed]
Graham, FL; van der Eb, AJ. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. [PubMed]
Green, S; Issemann, I; Sheer, E. A versatile in vivo and in vitro eukaryotic expression vector for protein engineering. Nucleic Acids Res. 1988 Jan 11;16(1):369–369. [PubMed]
Holder, N; Hill, J. Retinoic acid modifies development of the midbrain-hindbrain border and affects cranial ganglion formation in zebrafish embryos. Development. 1991 Dec;113(4):1159–1170. [PubMed]
Hunt, P; Gulisano, M; Cook, M; Sham, MH; Faiella, A; Wilkinson, D; Boncinelli, E; Krumlauf, R. A distinct Hox code for the branchial region of the vertebrate head. Nature. 1991 Oct 31;353(6347):861–864. [PubMed]
Jones, FS; Prediger, EA; Bittner, DA; De Robertis, EM; Edelman, GM. Cell adhesion molecules as targets for Hox genes: neural cell adhesion molecule promoter activity is modulated by cotransfection with Hox-2.5 and -2.4. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2086–2090. [PubMed]
Kerner, SA; Scott, RA; Pike, JW. Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4455–4459. [PubMed]
Kessel, M; Gruss, P. Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell. 1991 Oct 4;67(1):89–104. [PubMed]
Kumar, V; Chambon, P. The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer. Cell. 1988 Oct 7;55(1):145–156. [PubMed]
Kunkel, TA; Roberts, JD; Zakour, RA. Rapid and efficient site-specific mutagenesis without phenotypic selection. Methods Enzymol. 1987;154:367–382. [PubMed]
Kuo, CJ; Mendel, DB; Hansen, LP; Crabtree, GR. Independent regulation of HNF-1 alpha and HNF-1 beta by retinoic acid in F9 teratocarcinoma cells. EMBO J. 1991 Aug;10(8):2231–2236. [PubMed]
Lammer, EJ; Chen, DT; Hoar, RM; Agnish, ND; Benke, PJ; Braun, JT; Curry, CJ; Fernhoff, PM; Grix, AW, Jr; Lott, IT, et al. Retinoic acid embryopathy. N Engl J Med. 1985 Oct 3;313(14):837–841. [PubMed]
LaRosa, GJ; Gudas, LJ. Early retinoic acid-induced F9 teratocarcinoma stem cell gene ERA-1: alternate splicing creates transcripts for a homeobox-containing protein and one lacking the homeobox. Mol Cell Biol. 1988 Sep;8(9):3906–3917. [PubMed]
Leid, M; Kastner, P; Lyons, R; Nakshatri, H; Saunders, M; Zacharewski, T; Chen, JY; Staub, A; Garnier, JM; Mader, S, et al. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell. 1992 Jan 24;68(2):377–395. [PubMed]
Le Mouellic, H; Lallemand, Y; Brûlet, P. Homeosis in the mouse induced by a null mutation in the Hox-3.1 gene. Cell. 1992 Apr 17;69(2):251–264. [PubMed]
Leroy, P; Nakshatri, H; Chambon, P. Mouse retinoic acid receptor alpha 2 isoform is transcribed from a promoter that contains a retinoic acid response element. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10138–10142. [PubMed]
Lufkin, T; Dierich, A; LeMeur, M; Mark, M; Chambon, P. Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell. 1991 Sep 20;66(6):1105–1119. [PubMed]
Malicki, J; Cianetti, LC; Peschle, C; McGinnis, W. A human HOX4B regulatory element provides head-specific expression in Drosophila embryos. Nature. 1992 Jul 23;358(6384):345–347. [PubMed]
Mangelsdorf, DJ; Borgmeyer, U; Heyman, RA; Zhou, JY; Ong, ES; Oro, AE; Kakizuka, A; Evans, RM. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev. 1992 Mar;6(3):329–344. [PubMed]
Marks, MS; Hallenbeck, PL; Nagata, T; Segars, JH; Appella, E; Nikodem, VM; Ozato, K. H-2RIIBP (RXR beta) heterodimerization provides a mechanism for combinatorial diversity in the regulation of retinoic acid and thyroid hormone responsive genes. EMBO J. 1992 Apr;11(4):1419–1435. [PubMed]
McGinnis, W; Krumlauf, R. Homeobox genes and axial patterning. Cell. 1992 Jan 24;68(2):283–302. [PubMed]
Morgan, BA; Izpisúa-Belmonte, JC; Duboule, D; Tabin, CJ. Targeted misexpression of Hox-4.6 in the avian limb bud causes apparent homeotic transformations. Nature. 1992 Jul 16;358(6383):236–239. [PubMed]
Morriss-Kay, G; Tucket, F. Early events in mammalian craniofacial morphogenesis. J Craniofac Genet Dev Biol. 1991 11(4):181–191.Oct–Dec; [PubMed]
Morriss-Kay, GM; Murphy, P; Hill, RE; Davidson, DR. Effects of retinoic acid excess on expression of Hox-2.9 and Krox-20 and on morphological segmentation in the hindbrain of mouse embryos. EMBO J. 1991 Oct;10(10):2985–2995. [PubMed]
Murphy, SP; Garbern, J; Odenwald, WF; Lazzarini, RA; Linney, E. Differential expression of the homeobox gene Hox-1.3 in F9 embryonal carcinoma cells. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5587–5591. [PubMed]
Noda, M; Vogel, RL; Craig, AM; Prahl, J; DeLuca, HF; Denhardt, DT. Identification of a DNA sequence responsible for binding of the 1,25-dihydroxyvitamin D3 receptor and 1,25-dihydroxyvitamin D3 enhancement of mouse secreted phosphoprotein 1 (SPP-1 or osteopontin) gene expression. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9995–9999. [PubMed]
Nordeen, SK. Luciferase reporter gene vectors for analysis of promoters and enhancers. Biotechniques. 1988 May;6(5):454–458. [PubMed]
Papalopulu, N; Clarke, JD; Bradley, L; Wilkinson, D; Krumlauf, R; Holder, N. Retinoic acid causes abnormal development and segmental patterning of the anterior hindbrain in Xenopus embryos. Development. 1991 Dec;113(4):1145–1158. [PubMed]
Papalopulu, N; Lovell-Badge, R; Krumlauf, R. The expression of murine Hox-2 genes is dependent on the differentiation pathway and displays a collinear sensitivity to retinoic acid in F9 cells and Xenopus embryos. Nucleic Acids Res. 1991 Oct 25;19(20):5497–5506. [PubMed]
Pöpperl, H; Featherstone, MS. An autoregulatory element of the murine Hox-4.2 gene. EMBO J. 1992 Oct;11(10):3673–3680. [PubMed]
Pratt, MA; Kralova, J; McBurney, MW. A dominant negative mutation of the alpha retinoic acid receptor gene in a retinoic acid-nonresponsive embryonal carcinoma cell. Mol Cell Biol. 1990 Dec;10(12):6445–6453. [PubMed]
Ruberte, E; Dolle, P; Chambon, P; Morriss-Kay, G. Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos. Development. 1991 Jan;111(1):45–60. [PubMed]
Sadoul, R; Featherstone, MS. Sequence analysis of the homeobox-containing exon of the murine Hox-4.3 homeogene. Biochim Biophys Acta. 1991 Jun 13;1089(2):259–261. [PubMed]
Sham, MH; Hunt, P; Nonchev, S; Papalopulu, N; Graham, A; Boncinelli, E; Krumlauf, R. Analysis of the murine Hox-2.7 gene: conserved alternative transcripts with differential distributions in the nervous system and the potential for shared regulatory regions. EMBO J. 1992 May;11(5):1825–1836. [PubMed]
Simeone, A; Acampora, D; Arcioni, L; Andrews, PW; Boncinelli, E; Mavilio, F. Sequential activation of HOX2 homeobox genes by retinoic acid in human embryonal carcinoma cells. Nature. 1990 Aug 23;346(6286):763–766. [PubMed]
Simeone, A; Acampora, D; Nigro, V; Faiella, A; D'Esposito, M; Stornaiuolo, A; Mavilio, F; Boncinelli, E. Differential regulation by retinoic acid of the homeobox genes of the four HOX loci in human embryonal carcinoma cells. Mech Dev. 1991 Mar;33(3):215–227. [PubMed]
Smith, SM; Eichele, G. Temporal and regional differences in the expression pattern of distinct retinoic acid receptor-beta transcripts in the chick embryo. Development. 1991 Jan;111(1):245–252. [PubMed]
Stumpf, WE. Vitamin D--soltriol the heliogenic steroid hormone: somatotrophic activator and modulator. Discoveries from histochemical studies lead to new concepts. Histochemistry. 1988;89(3):209–219. [PubMed]
Tabin, CJ. Retinoids, homeoboxes, and growth factors: toward molecular models for limb development. Cell. 1991 Jul 26;66(2):199–217. [PubMed]
Tuggle, CK; Zakany, J; Cianetti, L; Peschle, C; Nguyen-Huu, MC. Region-specific enhancers near two mammalian homeo box genes define adjacent rostrocaudal domains in the central nervous system. Genes Dev. 1990 Feb;4(2):180–189. [PubMed]
Umesono, K; Murakami, KK; Thompson, CC; Evans, RM. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell. 1991 Jun 28;65(7):1255–1266. [PubMed]
Vasios, G; Mader, S; Gold, JD; Leid, M; Lutz, Y; Gaub, MP; Chambon, P; Gudas, L. The late retinoic acid induction of laminin B1 gene transcription involves RAR binding to the responsive element. EMBO J. 1991 May;10(5):1149–1158. [PubMed]
Violette, SM; Shashikant, CS; Salbaum, JM; Belting, HG; Wang, JC; Ruddle, FH. Repression of the beta-amyloid gene in a Hox-3.1-producing cell line. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3805–3809. [PubMed]
Wagner, M; Thaller, C; Jessell, T; Eichele, G. Polarizing activity and retinoid synthesis in the floor plate of the neural tube. Nature. 1990 Jun 28;345(6278):819–822. [PubMed]
Webster, WS; Ritchie, HE. Teratogenic effects of alcohol and isotretinoin on craniofacial development: an analysis of animal models. J Craniofac Genet Dev Biol. 1991 11(4):296–302.Oct–Dec; [PubMed]
Yu, VC; Delsert, C; Andersen, B; Holloway, JM; Devary, OV; Näär, AM; Kim, SY; Boutin, JM; Glass, CK; Rosenfeld, MG. RXR beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell. 1991 Dec 20;67(6):1251–1266. [PubMed]
Zappavigna, V; Renucci, A; Izpisúa-Belmonte, JC; Urier, G; Peschle, C; Duboule, D. HOX4 genes encode transcription factors with potential auto- and cross-regulatory capacities. EMBO J. 1991 Dec;10(13):4177–4187. [PubMed]
Zelent, A; Krust, A; Petkovich, M; Kastner, P; Chambon, P. Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. Nature. 1989 Jun 29;339(6227):714–717. [PubMed]
Zhang, XK; Hoffmann, B; Tran, PB; Graupner, G; Pfahl, M. Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors. Nature. 1992 Jan 30;355(6359):441–446. [PubMed]