Gene expression regulation by retinoic acid

Over the last quarter century, more than 532 genes have been put forward as regulatory targets of retinoic acid. In some cases this control is direct, driven by a liganded heterodimer of retinoid receptors bound to a DNA response element; in others, it is indirect, reflecting the actions of intermediate transcription factors, non-classical associations of receptors with other proteins, or even more distant mechanisms. Given the broad range of scientific questions continually under investigation, researchers do not always have occasion to classify target genes along these lines. However, our understanding of the genetic role of retinoids will be enhanced if such a distinction can be made for each regulated gene. We have therefore evaluated published data from 1,191 papers covering 532 genes and have classified these genes into four categories according to the degree to which an hypothesis of direct versus indirect control is supported overall.We found 27 genes that are unquestionably direct targets of the classical pathway in permissive cellular contexts (Category 3 genes), plus 105 genes that appear to be candidates, pending the results of specific additional experiments (Category 2). Data on another 267 targets are not evocative of direct or indirect regulation either way, although control by retinoic acid through some mechanism is clear (Category 1). Most of the remaining 133 targets seem to be regulated indirectly, usually through a transcriptional intermediary, in the contexts studied so far (Category 0). Over the last quarter century, more than 532 genes have been put forward as regulatory targets of retinoic acid. In some cases this control is direct, driven by a liganded heterodimer of retinoid receptors bound to a DNA response element; in others, it is indirect, reflecting the actions of intermediate transcription factors, non-classical associations of receptors with other proteins, or even more distant mechanisms. Given the broad range of scientific questions continually under investigation, researchers do not always have occasion to classify target genes along these lines. However, our understanding of the genetic role of retinoids will be enhanced if such a distinction can be made for each regulated gene. We have therefore evaluated published data from 1,191 papers covering 532 genes and have classified these genes into four categories according to the degree to which an hypothesis of direct versus indirect control is supported overall. We found 27 genes that are unquestionably direct targets of the classical pathway in permissive cellular contexts (Category 3 genes), plus 105 genes that appear to be candidates, pending the results of specific additional experiments (Category 2). Data on another 267 targets are not evocative of direct or indirect regulation either way, although control by retinoic acid through some mechanism is clear (Category 1). Most of the remaining 133 targets seem to be regulated indirectly, usually through a transcriptional intermediary, in the contexts studied so far (Category 0). BackgroundBeginning in at least the late 1960s, there was tremendous interest in whether the differentiating and tumor suppressing activities of retinoids reflected a genetic mechanism, on analogy to the steroid hormones, or an epigenetic one. It had been known for some time that retinoids could influence mRNA levels in certain cells, but also that they could increase activity on membrane-bound ribosomes. Any number of different mechanisms were possible, and quite a few were proposed. In a particularly prescient statement of 1976, Sani and Hill (1Sani B.P. Hill D.L. A retinoic acid-binding protein from chick embryo skin.Cancer Res. 1976; 36: 409-413Google Scholar) wrote, “The action of retinoic acid in reversing preneoplastic and neoplastic lesions may be due to a hormone-like effect involving induction and/or suppression of gene activity.” However, no conclusive experimental evidence had yet been adduced. As far as we know, it was Blalock and Gifford (2Blalock J.E. Gifford G.E. Retinoic acid (vitamin A acid) induced transcriptional control of interferon production.Proc. Natl. Acad. Sci. USA. 1977; 74: 5382-5386Google Scholar) who first provided such evidence when they showed, in 1977, that interferon synthesis can be suppressed at a transcriptional level by a protein induced by all-trans retinoic acid (RA). To make their case they used transcription blockers, protein synthesis inhibitors, and a kinetic argument.It is now known that RA can influence gene expression and protein production in many ways, but in terms of molecular mechanisms, a single, predominant, classical pathway has emerged: all-trans retinoic acid plus a dimer composed of a retinoic acid receptor and a retinoid X receptor (an RAR.RXR dimer) and a more or less regular DNA response element. In this paper, genes that respond through this pathway are called “direct” targets of the classical RA pathway; those that respond to RA through other molecular mechanisms, but do respond, are called “indirect” targets. Since Blalock and Gifford's paper nearly a quarter century ago, more than 532 genes have been put forward as regulatory targets of RA; and while the distinction between direct and indirect regulation is now well entrenched, it is not necessarily germane to every study. Nevertheless, a great deal of suggestive data has been generated and it can be used to construct a tentative classification of RA's targets along these lines.Constructing a classification tableThere is a simple but powerful motivation for constructing such a classification: progress in understanding RA's role at a genomic or proteomic level will require determining which regulatory events are handled through which cellular circuits. This paper is an attempt to begin that process in a systematic way. In what follows, we have evaluated the experimental evidence presented in more than 1,191 published articles and have prepared a preliminary categorization of RA's targets according to the degree to which current research supports an hypothesis of direct versus indirect control. More specifically, we have constructed a table (see Gene Table at the end of this article) that briefly summarizes the experimental evidence available for each target gene and “rates” the degree to which the combined evidence supports or opposes the notion of direct regulation in at least one cellular context. Where the evidence is very strong, constituting proof or something close to it, we call the gene a Category 3 gene. Where the combined evidence suggests or demonstrates indirect regulation (in the contexts studied, and no other investigations show or suggest direct regulation elsewhere), we have called the gene a Category 0 gene. Categories 1 and 2 are positioned between these two, with the evidence for direct regulation somewhat stronger for Category 2 genes. All four categories are more rigorously characterized below.It should be stressed that the numeric designations used for the categories are nothing more than tags. With a very few exceptions (which always clearly marked), the Category 0 genes are regulatory targets of RA every bit as much as Category 3 genes. They are simply regulated in different ways. Category 1 and Category 2 genes are also targets, although current research does not allow us to conclude quite so much about the mechanisms employed in these cases. Emphatically, the classification does not mean to impugn the work reported in the any of papers considered. The distinction between direct and indirect regulation is not necessarily relevant to many valid research goals, and a great deal of valuable work has been done in clinical, developmental, and basic science without addressing these questions even obliquely.Of necessity, the Gene Table is long and complex. However, the genome projects, various proteomic studies, and the preliminary gene ontologies produced over the last few years have made it clear that work on some very interesting biological questions will require dealing with vast amounts of data. Gene expression regulation by RA encompasses a number of such questions and a compilation like the Gene Table would seem to be an economical way to approach some of them.The classical RA pathwayFour basic concepts are central to any description of the classical RA pathway: ligand involvement, receptor dimerization, DNA binding, and the resulting transcriptional modulation of the gene (occasionally, one of the genes) whose regulatory element has been bound. It sometimes happens that the gene under investigation is not the gene whose regulatory unit has been bound, but that RA has regulated an intermediary which in turn regulates the gene of interest. In these cases, the intermediary factor (usually another transcription factor) may be a direct target, while the gene under study is an indirect target. Other types of indirect regulation include RA's ability to influence mRNA stability, to activate nuclear receptor dimers other than an RAR.RXR, and so forth.It might seem arbitrary, uninformative, or unnecessarily stringent to restrict “direct” regulation to the classical RA pathway and to consign all other regulatory modalities to the catch-all category, “indirect” regulation. However, each alternative regulatory pathway represents a distinct type of genetic event. Perhaps each deserves its own Gene Table. We chose the classical RA pathway as a branch point in the present work, i) because of its preeminent historical position, ii) because the distinction between direct and indirect regulation through this pathway is well established and frequently studied, and iii) because many suggestive and highly relevant studies are available, even though questions of molecular mechanism are not necessarily raised in them.The Gene Table is intended to cover every gene now known to be regulated by retinoic acid. The last attempt at delineating a complete set of such genes was published by Chytil and Raiz-ul-Haq in 1990 (3Chytil F. Riaz-ul-Haq Vitamin A mediated gene expression.Crit. Rev. Eukaryot. Gene Expr. 1990; 1: 61-73Google Scholar). They listed more than 125 proteins that we now take to be monogenic, plus a number of other proteins of less clear provenance. Gudas et al. took a slightly different starting point 4 years later, and wrote detailed descriptions of most RA targets known at the time. They categorized them primarily along functional or homology lines (4Gudas L.J. Roberts A.B. Sporn M.B. Cellular biology and biochemistry of the retinoids.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. 2nd Edition. Raven Press, New York1994: 443-520Google Scholar).Literature reviewsRetinoid science is an immense field. Two recent reviews, both of which are comprehensive within their scopes but neither of which attempts a complete list of RA-regulated genes, are by Nagpal and Chandraratna (5Nagpal S. Chandraratna R.A. Vitamin A and regulation of gene expression.Curr. Opin. Clin. Nutr. Metab. Care. 1998; 1: 341-346Google Scholar) and a cross-lab group led by De Luca (6Ross S.A. McCaffery P.J. Drager U.C. De Luca L.M. Retinoids in embryonal development.Physiol. Rev. 2000; 80: 1021-1054Google Scholar). Two more specialized reviews, on receptor-specific ligands (7Nagpal S. Chandraratna R.A. Recent developments in receptor-selective retinoids.Curr. Pharm. Des. 2000; 6: 919-931Google Scholar) and on discoveries made through receptor knockouts (8Mark M. Ghyselinck N.B. Wendling O. Dupe V. Mascrez B. Kastner P. Chambon P. A genetic dissection of the retinoid signalling pathway in the mouse.Proc. Nutr. Soc. 1999; 58: 609-613Google Scholar), expand on topics that turn up frequently in the Gene Table, but are treated only generically. Beyond these, virtually every area of regulatory, clinical, and developmental application has its own reviews. To mention just a few, see (9Petkovich P.M. Retinoic acid metabolism.J. Am. Acad. Dermatol. 2001; 45: S136-S142Google Scholar) for retinoid metabolism, (10Kurie J.M. The biologic basis for the use of retinoids in cancer prevention and treatment.Curr. Opin. Oncol. 1999; 11: 497-502Google Scholar) for retinoids and cancer, (11Gavalas A. Krumlauf R. Retinoid signalling and hindbrain patterning.Curr. Opin. Genet. Dev. 2000; 10: 380-386Google Scholar) or (12Schier A.F. Axis formation and patterning in zebrafish.Curr. Opin. Genet. Dev. 2001; 11: 393-404Google Scholar) for two topics in developmental work, and (13Zouboulis C.C. Retinoids–which dermatological indications will benefit in the near future?.Skin Pharmacol. Appl. Skin Physiol. 2001; 14: 303-315Google Scholar) for dermatological issues. An updated collection of methods papers has recently been published. It contains valuable information on traditional as well as innovative experimental techniques involving the retinoids, their receptors, and associated molecules. See (14Barua A.B. Furr H.C. Properties of retinoids. Structure, handling, and preparation.Methods Mol. Biol. 1998; 89: 3-28Google Scholar) and the papers following it. A detailed characterization of what is currently known about the molecular and even atomic mechanisms that permit direct RA-activated transcriptional regulation is presented in (15Gronemeyer H. Miturski R. Molecular mechanisms of retinoid action.Cell. Mol. Biol. Lett. 2001; 6: 3-52Google Scholar). Although these events are beyond the scope of the present paper, they underpin many of the routes of gene regulation covered here.The retinoid receptors are members of a much larger group of transcription factors, the so-called nuclear receptors. An encyclopedic overview of this large and important class of proteins is Gronemeyer and Laudet's 1995 monograph (16Gronemeyer H. Laudet V. Transcription factors 3: nuclear receptors.Protein Profile. 1995; 2: 1173-1308Google Scholar). It remains invaluable even though its publication preceded some of the more recent work on co-regulators, intermediary factors, and the chromatin connection. For an update in those areas, see Rosenfeld and Glass (17Rosenfeld M.G. Glass C.K. Coregulator codes of transcriptional regulation by nuclear receptors.J. Biol. Chem. 2001; 276: 36865-36868Google Scholar). Chawla et al. (18Chawla A. Repa J.J. Evans R.M. Mangelsdorf D.J. Nuclear receptors and lipid physiology: opening the X-files.Science. 2001; 294: 1866-1870Google Scholar) recently reviewed the connection between the nuclear receptors and lipid physiology, and both RARs and RXRs play roles in this. Finally, two collections of particularly noteworthy reviews appeared in the mid-1990s: one covering various aspects of the nuclear receptors and the other, various aspects of the retinoids. See (19Mangelsdorf D.J. Thummel C. Beato M. Herrlich P. Schutz G. Umesono K. Blumberg B. Kastner P. Mark M. Chambon P. The nuclear receptor superfamily: the second decade.Cell. 1995; 83: 835-839Google Scholar) and (20Bollag W. The retinoid revolution. Overview.FASEB J. 1996; 10: 938-939Google Scholar), respectively, and the articles that accompany them.METHODSSelecting genes for inclusion in this analysisThe Gene Table does not cover every gene ever investigated in conjunction with retinoic acid, although we hope it includes every known target. Because RA has the power to initiate fundamental phenotypic changes in many cells, it is sometimes used only as an agent to set up an experiment: differentiated versus non-differentiated cells, for example. Genes investigated only in such settings were excluded. Overall, our basic filter for including or excluding genes was whether or not an explicit claim of regulation by retinoic acid had been advanced. We did not require that the regulation be attributed to the classical RA pathway. In some cases, direct regulation was investigated or implied; in others it was indirect regulation; and in some, the mode of regulation was not addressed, either explicitly or implicitly.Although we made every effort to identify and follow up on “novel” genes identified in differential display-type experiments, we have not included any genes so totally uncharacterized that they have not yet even been named. See (21Chen Y. Talmage D.A. Subtractive cDNA cloning and characterization of genes induced by all-trans retinoic acid.Ann. N. Y. Acad. Sci. 1999; 886: 225-228Google Scholar) for some examples. Nor have we included fragments so far identified only as ESTs. See (22Wang K.C. Cheng A.L. Chuang S.E. Hsu H.C. Su I.J. Retinoic acid-induced apoptotic pathway in T-cell lymphoma: Identification of four groups of genes with differential biological functions.Exp. Hematol. 2000; 28: 1441-1450Google Scholar) and (23Qiu H. Zhang W. El Naggar A.K. Lippman S.M. Lin P. Lotan R. Xu X.C. Loss of retinoic acid receptor-beta expression is an early event during esophageal carcinogenesis.Am. J. Pathol. 1999; 155: 1519-1523Google Scholar) for examples of these.An analysis of this sort would ideally be limited to work done in “normal” cells or individuals; the activities of RA and its receptors in aberrant cell types would then be handled separately as exceptions. We have tried to do this up to a point. Work on cells that have suffered catastrophic DNA events that are likely to have affected RA's activity, certain viral integrations, extraordinary recombinations, engineering experiments, and the like, have been excluded except to make occasional special points. In particular, work on acute promyelocytic leukemia (APL) cells, which generally express oncogenic RARα fusions, have been largely excluded on this ground. Nevertheless, a great deal of research has been done on RA's activities in APL cells and we refer the reader to (24Pandolfi P.P. Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia.Hum. Mol. Genet. 2001; 10: 769-775Google Scholar) for a review. Of course, many common cell lines contain genomic anomalies that are not likely to have affected RA's activity overall: HepG2 and Caco-2 lines, for example. For the purposes of this work, such cell lines are considered normal.As a rule, we did not consider experiments in which RA was used in conjunction with another treatment, although we tried to take note of any controls using RA alone. The exception to this is where some form of external “activation” seems to be required for any expression of the target gene, for example, the interleukins. It should be stressed that by excluding combo-treatments we automatically ruled out many studies using RA plus cAMP (or RA plus cAMP and theophylline) rather than RA alone. We did, however, consider these experiments if they confirmed points suggested elsewhere by RA alone. This is an admitted limitation of the present work, but the complexity of regulatory interactions in these cases is still overwhelming.Constructing a database of papers and genesUsing various free text and MeSH (Medical Subject Headings) strategies at the United States National Library of Medicine's PubMed gateway, we created a database of more than 4,000 papers relevant to the regulation of gene expression by retinoic acid. We identified the gene or genes considered in each paper, and, based on abstracts, selected what appeared to be the most relevant studies for each gene. Using this set of abstracts and the associated MEDLINE coding, we determined which species had been investigated, located the gene's official name at LocusLink (25Pruitt K.D. Maglott D.R. RefSeq and LocusLink: NCBI gene-centered resources.Nucleic Acids Res. 2001; 29: 137-140Google Scholar), and performed supplementary searches based on official nomenclature, curated aliases, and any novel names or aliases applied to orthologs. This process was iterated as necessary, and eventually led to a list of relevant papers for each gene. These entries were then re-evaluated at the abstract level and the most promising papers (for our purposes) were gathered and consulted for data, discussions, and further citations. New candidate genes went through the same process as they turned up. By the end of the project, nearly 8,000 papers (not including reviews) had been considered to one degree or another.For each gene, we then studied the scientific evidence presented in the selected papers and evaluated the degree to which a direct regulatory pathway had been demonstrated, suggested, or brought into question. This information was distilled into several short standardized phrases and incorporated into the Gene Table, along with species information, any alternative names and symbols used in the selected studies, and references to the most essential papers.Concordance of working and official gene namesMost genes have several names. By “official nomenclature” we mean names and symbols approved by (or pending before) the Human Genome Organization Nomenclature Committee, the Mouse Genome Informatics Nomenclature Committee, the International Rat Genetic Nomenclature Committee, or the Zebrafish Nomenclature Committee. We have followed official nomenclature whenever possible. This can be confusing when the official name of a gene is either uninformative, uncommon, or simply designed for a purpose that is not one's own. For example, most readers probably would not recognize Nr2f1 as the name of the gene that encodes COUP-1. However, while understandable from a historical perspective, the proliferation of trivial names (for both genes and proteins) has been scientifically unhelpful and using official names solves the problem. The lists of alternatives and aliases kept by the nomenclature committees and at LocusLink should quickly resolve any questions.It is not always easy to determine which gene has been studied in a given paper, or which papers deal with the same gene; and this is not limited to older papers. It can be particularly problematic when several species, or several apparently unrelated scientific questions, have been studied in different papers. In a number of cases, we had to align published primer sequences with groups of homologs, follow LinkOuts to cited sequences at the National Center for Biotechnology Information's Entrez system, or even BLAST nucleotides strings taken from journal figures.As a rule, the Gene Table uses the gene symbol from the species discussed in the earliest paper cited; when no approved, pending, or interim name was available for the gene in that species, we generally chose the mouse version. The nomenclature committees try to keep symbols and leading phrases invariant over vertebrate species (except for orthographic differences) so this is little more than a matter of choice. In order to save space, only symbols, not full names, are used in the first column of the table.Trivial names from cited papersThe second column of the Gene Table, “Name in refs,” lists only the gene or protein designations used in the papers cited. It does not include other aliases, no matter how common they may be in the literature. Table 1 provides a concordance between these working names (or abbreviations) and the symbols used in the Gene Table, but only for cases where the two are very different. Throughout, we have suppressed the distinction between genes and the proteins they encode.TABLE 1Concordance of trivial names and symbolsCommon NameGene Table14.5-D lectinLgals125-hydroxyvitamin D3-24-hydroxylaseCYP2434 kDa lectinLgals392 kDa gelatinaseMMP9A4CltaACSFACL2Activin AINHBAAcyl-coA synthaseFACL2ADD1Srebf1ADH3ADH1CAggrecanaseADAMTS4α 1-microglobulinAmbpα-SMActa2Aminopeptidase-BRNPEPAML2RUNX3ANFNppaANPNppaAntithrombin IIISERPINC1AP-2TFAP2AAP-2.2Tcfap2cAp-BRNPEPApolipoprotein(a)LPAARP-1Nr2f 2ArrestinSAGATXENPP2β 1-ARAdrb1β-amyloid precursor proteinAppBone sialoprotein (BSP)IBSPBone sialoprotein ISpp1Brn-3.2Pou4f 2c-ablAbl1Calcineurin APPP3CACalcineurin BPPP3CBCBFA3RUNX3CD10MMECD11aITGALCD11bITGAMCD15Fut4CD157BST1CD18ITGB2CD23FCER2CD31PECAM1CD43SPNCD50ICAM3CD51ItgavCD71TFRCCD82KAI1CD95PTPN13CD95TNFRSF6CD95 ligandTnfsf6c-fmsCSF1RCg BChgbCGRPCal1Cholesterol sulfotransferaseSULT2B1CIP1Cdkn1aCL-20EMP1clusterinTrpm2c-mybMYBc-mycMYCCollagenaseMMP1Connexin31Gjb3Connexin43Gja1ContactGdf 5CornifinSPRR1BCOUP-TF IINr2f 2COUP-TF1Nr2f1COX-1Ptgs1COX-2PTGS2CRBPIRbp1CRBPIIRbp2CTCal1Common NameGene TableCu/Zn superoxide dismutaseSod1Cx43Gja1Cyclin D3CCND3Cyclin ECcne1Cyclooxygenase-1Ptgs1D3Dio3D9Stra13DEAD box proteinDDX1DEAD box protein p72DDX17D-IIIDio3Dopamine D2 receptorDrd2DOROPRD1Drg1NDRG1Dystroglycan α, βDAG1E3Laptm5EATMCL1E-cadherinCDH1E-MAP-115Mtap7EndoAKRT8EndoBKRT18EndolynCd164eNOSNOS3EpithelinGrnERA-1Hoxa1Erk2Mapk1ET-1EDN1F1NgpF3Cntn1FAKPTK2FasTNFRSF6FasLTnfsf6FATPSLC27A1FBPase isozymeFbp2FGF-BPHBP17Focal adhesian kinasePTK2Fra-1Fosl1Fru-1, 6-P2aseFbp1Galectin-7LGALS7GCNFNr6a1Gelatinase AMMP2Gene 33MIG-6GLUT 2Slc2a2GLUT 3Slc2a3gp91-phoxCYBBgp96TRA1GRNR3C1GST 5.7Gsta4H218Gpcr13HAKR eAKR1C3HB-EGFDTRHER4ERBB4HERGKCNH2HGFLMST1HIOMTASMThlx-1dbx1aHNF-1 αTcf1HNF-1 βTcf2HNF-3 βFoxa2HNF-3 αFoxa1Hox-1.6Hoxa1HOX3DHOXC5Hox-2.bHoxb4Hox-4.2Hoxd4hRDH-TBERDHLHSP86Hsp86-1HSP90Hsp86-1HSPCAHsp86-1HSPGSDC2Htf 9-a/RanBP1Ranbp1IAPALPIICECASP1OsteopontinSpp1OTOXTp15CDKN2Bp190 GAP-associated proteinArhgap5p21Cdkn1ap34(CDC2)CDC2P450RAICyp26p47-phoxNCF1p53Trp53p67-phoxNCF2p68 kinasePRKRp75NTRNgfrPACAPADCYAP1PACAP1 (Type I) receptorADCYAP1R1PACAP2 (Type II) receptorVIPR1PAFRPTAFRPAI-1SERPINE1PAI-2SERPINB2P-cadherinCDH3PCD5Pcp2PCDHXPCDH11PCDHYPCDH22PEPCKPck1PGHS1Ptgs1PGHS2PTGS2pgp1ABCB1PKPk3PKCPkcaPKC β 1PRKCB1Placental lactogenCSH1Plasminogen activator inhibitor 1SERPINE1Plasminogen activator inhibitor 2SERPINB2pRbAp46Rbbp7proinsulinINSpromyelocytic defensin-1DEFA1ProT αPTMAPsoriasinS100A7PTHrPPthlhRA28FXYD3Rae-28Edr1Rae-30Fbp2RbRB1RBPRBP4RC3NRGNRDHRsdr1Retinal fascinFSCN2Rex-1Zfp42Rh1RhoRIG1RARRES3RIHBMdkRIP140NRIP1RIS-1S100A7RMUC176Muc3Rod-specific opsinRhoRTPNDRG1RTRNr6a1S14ThrspSar1aSaraSCCEKLK7SCFKitlSgp-2Trpm2SLAPSLASPASftpa1SP-BSFTPBSP-CSFTPCSpr1SPRR1BSSATSatSSEA-1Fut4SSeCSAkap12ST3MMP11Stem cell factorKitlIkarosZnfn1a1IL-1b stimulating geneBIRC3Importin αKpna2INK4BCDKN2BiNOSNos2J6 serpinSerpinh1K2eKRT2AK6KRT6Ak-caseinCsnkK-FGFFGF4KOROprk1Krox-24Egr1L-14Lgals1L-34Lgals3Lamins A/CLmnaLeftyEbafLewis xFut4LFA-3CD58Liver/bone/kidney APAkp2l-mycMYCL1LNGFRNgfrLOX-1Olr1LPLLpll-selectinSELLMAC-1ITGAMMajor histocompatibility class I (H2K, -D, -L, -Q, etc.)H2MASH1Ascl1Mash-2Ascl2MCADACADMMCP-1SCYA2M-CSFCSF1mda-6Cdkn1aMDR1ABCB1mdr3ABCB1Meis2Mrg1MKMdkMLN/CAB1MLN64MnSODSOD2MOROPRM1Mox1Meox1mph1Edr1mrp2ABCC2MRP-8S100A8Msx-1Msx2mWnt-8Wnt8dMZF-1ZNF42Na, K-ATPaseAtp1a3Na+/H+ antiporterSLC9A1N-cadherinCDH2Ndr1NDRG1NEPMMENGFI-BNR4A1NHE-2Slc9a2NISSLC5A5NKX3.2Bapx1nm23-H1NME1NMDAR1GRIN1NN8-4AGRrg1nNOSNOS1NOR-1NR4A3NSP-ARTN1NSP-CRTN3ntcpSLC10A1Nur77NR4A1Nurr1NR4A2obLepOct3Pou5f1Oct3/4Pou5f1OPSpp1OsteocalcinBGLAPOsteonectinSparcStra1Efnb1Stra10Mrg1Stra11Wnt8dStra3EbafStra7Gbx2StromelysinMMP3Stromelysin-3MMP11SurvivinBIRC5TBRIITgfbr1TFF3TF CA150TAF2STfRTFRCTGase KTgm1TIG1RARRES1TIG2RARRES2TIG3RARRES3TIS10PTGS2Tissue factorF3TMTHBDTNAPAkp2TopoIITOP2At-PAPLATTR2-11Nr2c1TR4NR2C2TrkANtrk1TrkbNtrk2TrkCNTRK3TRP-2DCTUlipDPYSL3u-PAPLAUVAChTSlc18a3Vesicular acetylcholine transporterSlc18a3Vitronectin receptorItgavWAF1Cdkn1aXlim-1Lhx1Y1RNPY1Rzif 268Egr1Concordance of common names and the official symbols used in the Gene Table for cases where there are significant differences between them. Open table in a new tab Tabled 1SymbolName in RefsSppDirSummaryRef PMIDsCatADH1CADH3HsUpInduction; functional binding site; negative TRE nearby.0001996113; 0001321136; 00083881583CD38CD38Hs, MmUpInduction; differentiation controls; specific ligands; functional binding sites; evidence from transgenics.7690555; 0008394323; 0007511050; 0009160665; 0009624127; 109698053Cdx1Cdx1Mm, HsaUpInduction; conserved functional binding site.7649373; 109381323CEBPEC/EBP epsilonHsUpRapid induction during differentiation; functional binding site; specific ligands.9376579; 9177240; 00103304223CRABP2CRABP-IIHs, MmUpInduction; conserved functional binding sites.0001654334; 1309505; 0001313808; 0001327537; 0001334086; 0008071361; 00098568253CryabαB-crystallin/small HSPMmUpInduction; functional binding site.00096514023Drd2dopamine D2 receptorHs, Mm, RnUpInduction; functional binding site; evidence from transgenics.7990648; 0009405615; 0009721718; 94523863Egr1Egr-1, zif268, Krox-24Mm, RnUpInduction; functional binding site (characterized as a single half-site).1936556; 1793734; 1708092; 0007877619; 81762543ETS1Ets1, ets-1Hs, MmUpRapid induction during differentiation; functional binding motifs (single hexamer and DR5).3060792; 7689222; 0010773887; 113273093Foxa1HNF-3αMmUpRapid induction during differentiation; no protein synthesis required; functional binding site.8029022; 7649373; 9260895; 00103885163H1F0H1° histone, H1 degreeMm, HsUpEarly induction during differentiation; functional binding site (DR8); other NRs.2846273; 1988682; 0008078070; 0007576177; 00085596623Hoxa1ERA-1, Hox-1.6, Hoxa-1Mm, DrUpInduction; conserved functional binding site; whole animal evidence (including transgenics).0003422432; 0002906112; 0001360810; 0007743939; 0008631251; 0008999919; 00090533163HOXA4hoxa-4Hs, MmUpInduction; upstream functional binding site and downstream RA-responsive enhancer; whole animal evidence including transgenics; site conservation.0008759021; 0009570764; 9272954; 00106799303Hoxb1Hoxb-1Mm, Gg, Tr, HsvrsbInduction; functional binding sites (5′ and several 3′); whole animal evidence including transgenics; site conservation.0007914354; 0007916164; 0007831296; 0007831297; 0008999919; 0009463349; 0009671595; 00098692973Hoxb4Hox-2.6, Hoxb-4Mm, Tr, GgUpInduction; conserved functional binding site; evidence from transgenics.0007878040; 9272954; 00096978503Hoxd4Hox-4.2, Hoxd-4Mm, HsUpInduction; functional binding sites (5′ and several 3′); whole animal evidence including transgenics; site conservation; some dis