Multiple transcription factor codes activate epidermal wound–response genes in Drosophila
Open accessAbstract
Wounds in Drosophila and mouse embryos induce similar genetic pathways to repair epidermal barriers. However, the transcription factors that transduce wound signals to repair epidermal barriers are largely unknown. We characterize the transcriptional regulatory enhancers of 4 genes-Ddc, ple, msn, and kkv-that are rapidly activated in epidermal cells surrounding wounds in late Drosophila embryos and early larvae. These epidermal wound enhancers all contain evolutionarily conserved sequences matching binding sites for JUN/FOS and GRH transcription factors, but vary widely in trans- and cis-requirements for these inputs and their binding sites. We propose that the combination of GRH and FOS is part of an ancient wound-response pathway still used in vertebrates and invertebrates, but that other mechanisms have evolved that result in similar transcriptional output. A common, but largely untested assumption of bioinformatic analyses of gene regulatory networks is that transcription units activated in the same spatial and temporal patterns will require the same cis-regulatory codes. Our results indicate that this is an overly simplistic view.
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The integument cells that are tasked with wound repair and building the outer epidermis of insects and vertebrates use entirely different effector genes, but these genes are driven by the same regulatory factor.
“Similarly, the integument cells that are tasked with wound repair and building the outer epidermis of insects and vertebrates use entirely different effector genes, but these genes are driven by the same regulatory factor (21).”
From Transphyletic conservation of developmental regulatory state in animal evolution (2011) · cites this paper as [21]
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Wound healing recapitulates morphogenesis in Drosophila embryos
Wood, W., Jacinto, A., Grose, R., Woolner, S., Gale, J., Wilson, C., & Martin, P. (2002) · Nature Cell Biology · doi:10.1038/ncb875 · Cited by 435 · see citing works
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Research works printed but not linked: 59
- [1]Martin P, Parkhurst SM. Parallels between tissue repair and embryo morphogenesis. Development. 2004;131:3021–3034. doi: 10.1242/dev.01253. [DOI] [PubMed] [Google Scholar] · DOI
- [2]Martin P, Lewis J. Actin cables and epidermal movement in embryonic wound healing. Nature. 1992;360:179–183. doi: 10.1038/360179a0. [DOI] [PubMed] [Google Scholar] · DOI
- [3]McCluskey J, Martin P. Analysis of the tissue movements of embryonic wound healing–DiI studies in the limb bud stage mouse embryo. Dev Biol. 1995;170:102–114. doi: 10.1006/dbio.1995.1199. [DOI] [PubMed] [Google Scholar] · DOI
- [4]Brock J, Midwinter K, Lewis J, Martin P. Healing of incisional wounds in the embryonic chick wing bud: Characterization of the actin purse-string and demonstration of a requirement for Rho activation. J Cell Biol. 1996;135:1097–1107. doi: 10.1083/jcb.135.4.1097. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [6]Kiehart DP. Wound healing: The power of the purse string. Curr Biol. 1999;9:R602–R605. doi: 10.1016/s0960-9822(99)80384-4. [DOI] [PubMed] [Google Scholar] · DOI
- [7]Young PE, Richman AM, Ketchum AS, Kiehart DP. Morphogenesis in Drosophila requires nonmuscle myosin heavy chain function. Genes Dev. 1993;7:29–41. doi: 10.1101/gad.7.1.29. [DOI] [PubMed] [Google Scholar] · DOI
- [8]Williams-Masson EM, Malik AN, Hardin J. An actin-mediated two-step mechanism is required for ventral enclosure of the C. elegans hypodermis. Development. 1997;124:2889–2901. doi: 10.1242/dev.124.15.2889. [DOI] [PubMed] [Google Scholar] · DOI
- [9]Jacinto A, Martinez-Arias A, Martin P. Mechanisms of epithelial fusion and repair. Nat Cell Biol. 2001;3:E117–E123. doi: 10.1038/35074643. [DOI] [PubMed] [Google Scholar] · DOI
- [10]Hoffmann JA, Reichhart JM. Drosophila innate immunity: An evolutionary perspective. Nat Immunol. 2002;3:121–126. doi: 10.1038/ni0202-121. [DOI] [PubMed] [Google Scholar] · DOI
- [11]Mace KA, Pearson JC, McGinnis W. An epidermal barrier wound repair pathway in Drosophila is mediated by grainy head. Science. 2005;308:381–385. doi: 10.1126/science.1107573. [DOI] [PubMed] [Google Scholar] · DOI
- [12]Ting SB, et al. A homolog of Drosophila grainy head is essential for epidermal integrity in mice. Science. 2005;308:411–413. doi: 10.1126/science.1107511. [DOI] [PubMed] [Google Scholar] · DOI
- [13]Alibardi L. Structural and immunocytochemical characterization of keratinization in vertebrate epidermis and epidermal derivatives. Int Rev Cytol. 2006;253:177–259. doi: 10.1016/S0074-7696(06)53005-0. [DOI] [PubMed] [Google Scholar] · DOI
- [14]Galko MJ, Krasnow MA. Cellular and genetic analysis of wound healing in Drosophila larvae. PLoS Biol. 2004;2:E239. doi: 10.1371/journal.pbio.0020239. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [15]Cole J, Tsou R, Wallace K, Gibran N, Isik F. Early gene expression profile of human skin to injury using high-density cDNA microarrays. Wound Repair Regen. 2001;9:360–370. doi: 10.1046/j.1524-475x.2001.00360.x. [DOI] [PubMed] [Google Scholar] · DOI
- [16]Fitsialos G, et al. Transcriptional signature of epidermal keratinocytes subjected to in vitro scratch wounding reveals selective roles for ERK1/2, p38, and phosphatidylinositol 3-kinase signaling pathways. J Biol Chem. 2007;282:15090–15102. doi: 10.1074/jbc.M606094200. [DOI] [PubMed] [Google Scholar] · DOI
- [17]Stramer B, et al. Gene induction following wounding of wild-type versus macrophage-deficient Drosophila embryos. EMBO Rep. 2008;9:465–471. doi: 10.1038/embor.2008.34. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [18]Andersen SO, Hojrup P, Roepstorff P. Insect cuticular proteins. Insect Biochem Mol Biol. 1995;25:153–176. doi: 10.1016/0965-1748(94)00052-j. [DOI] [PubMed] [Google Scholar] · DOI
- [19]Uv AE, Thompson CR, Bray SJ. The Drosophila tissue-specific factor Grainyhead contains novel DNA-binding and dimerization domains which are conserved in the human protein CP2. Mol Cell Biol. 1994;14:4020–4031. doi: 10.1128/mcb.14.6.4020-4031.1994. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [20]Venkatesan K, McManus HR, Mello CC, Smith TF, Hansen U. Functional conservation between members of an ancient duplicated transcription factor family, LSF/Grainyhead. Nucleic Acids Res. 2003;31:4304–4316. doi: 10.1093/nar/gkg644. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [21]Pollock R, Treisman R. A sensitive method for the determination of protein-DNA binding specificities. Nucleic Acids Res. 1990;18:6197–6204. doi: 10.1093/nar/18.21.6197. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [22]Benbrook DM, Jones NC. Different binding specificities and transactivation of variant CRE's by CREB complexes. Nucleic Acids Res. 1994;22:1463–1469. doi: 10.1093/nar/22.8.1463. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [23]van Dijk MA, Murre C. Extradenticle raises the DNA binding specificity of homeotic selector gene products. Cell. 1994;78:617–624. doi: 10.1016/0092-8674(94)90526-6. [DOI] [PubMed] [Google Scholar] · DOI
- [24]Van Dijk MA, Voorhoeve PM, Murre C. Pbx1 is converted into a transcriptional activator upon acquiring the N-terminal region of E2A in pre-B-cell acute lymphoblastoid leukemia. Proc Natl Acad Sci USA. 1993;90:6061–6065. doi: 10.1073/pnas.90.13.6061. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [25]Neuteboom ST, Murre C. Pbx raises the DNA binding specificity but not the selectivity of antennapedia Hox proteins. Mol Cell Biol. 1997;17:4696–4706. doi: 10.1128/mcb.17.8.4696. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [26]Ekker SC, Young KE, von Kessler DP, Beachy PA. Optimal DNA sequence recognition by the Ultrabithorax homeodomain of Drosophila. EMBO J. 1991;10:1179–1186. doi: 10.1002/j.1460-2075.1991.tb08058.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [27]Pearson JC, Lemons D, McGinnis W. Modulating Hox gene functions during animal body patterning. Nat Rev Genet. 2005;6:893–904. doi: 10.1038/nrg1726. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- [28]Fried M, Crothers DM. Equilibria and kinetics of lac repressor-operator interactions by polyacrylamide gel electrophoresis. Nucleic Acids Res. 1981;9:6505–6525. doi: 10.1093/nar/9.23.6505. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [29]Perkins KK, Dailey GM, Tjian R. Novel Jun- and Fos-related proteins in Drosophila are functionally homologous to enhancer factor AP-1. EMBO J. 1988;7:4265–4273. doi: 10.1002/j.1460-2075.1988.tb03324.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [30]Ostrowski S, Dierick HA, Bejsovec A. Genetic control of cuticle formation during embryonic development of Drosophila melanogaster. Genetics. 2002;161:171–182. doi: 10.1093/genetics/161.1.171. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [31]Moussian B, Schwarz H, Bartoszewski S, Nusslein-Volhard C. Involvement of chitin in exoskeleton morphogenesis in Drosophila melanogaster. J Morphol. 2005;264:117–130. doi: 10.1002/jmor.10324. [DOI] [PubMed] [Google Scholar] · DOI
- [32]Su YC, Treisman JE, Skolnik EY. The Drosophila Ste20-related kinase misshapen is required for embryonic dorsal closure and acts through a JNK MAPK module on an evolutionarily conserved signaling pathway. Genes Dev. 1998;12:2371–2380. doi: 10.1101/gad.12.15.2371. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [33]Merzendorfer H, Zimoch L. Chitin metabolism in insects: structure, function and regulation of chitin synthases and chitinases. J Exp Biol. 2003;206:4393–4412. doi: 10.1242/jeb.00709. [DOI] [PubMed] [Google Scholar] · DOI
- [34]Ramet M, Lanot R, Zachary D, Manfruelli P. JNK signaling pathway is required for efficient wound healing in Drosophila. Dev Biol. 2002;241:145–156. doi: 10.1006/dbio.2001.0502. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- [35]Kosman D, et al. Multiplex detection of RNA expression in Drosophila embryos. Science. 2004;305:846. doi: 10.1126/science.1099247. [DOI] [PubMed] [Google Scholar] · DOI
- [36]Kockel L, Zeitlinger J, Staszewski LM, Mlodzik M, Bohmann D. Jun in Drosophila development: Redundant and nonredundant functions and regulation by two MAPK signal transduction pathways. Genes Dev. 1997;11:1748–1758. doi: 10.1101/gad.11.13.1748. [DOI] [PubMed] [Google Scholar] · DOI
- [37]Riesgo-Escovar JR, Hafen E. Common and distinct roles of DFos and DJun during Drosophila development. Science. 1997;278:669–672. doi: 10.1126/science.278.5338.669. [DOI] [PubMed] [Google Scholar] · DOI
- [38]Zeitlinger J, et al. Defective dorsal closure and loss of epidermal decapentaplegic expression in Drosophila fos mutants. EMBO J. 1997;16:7393–7401. doi: 10.1093/emboj/16.24.7393. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [39]Giesen K, et al. Regulation of glial cell number and differentiation by ecdysone and Fos signaling. Mech Dev. 2003;120:401–413. doi: 10.1016/s0925-4773(03)00009-1. [DOI] [PubMed] [Google Scholar] · DOI
- [40]Fassler J, et al. B-ZIP proteins encoded by the Drosophila genome: Evaluation of potential dimerization partners. Genome Res. 2002;12:1190–1200. doi: 10.1101/gr.67902. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [41]Bray SJ, Kafatos FC. Developmental function of Elf-1: An essential transcription factor during embryogenesis in Drosophila. Genes Dev. 1991;5:1672–1683. doi: 10.1101/gad.5.9.1672. [DOI] [PubMed] [Google Scholar] · DOI
- [42]Narasimha M, Uv A, Krejci A, Brown NH, Bray SJ. Grainy head promotes expression of septate junction proteins and influences epithelial morphogenesis. J Cell Sci. 2008;121:747–752. doi: 10.1242/jcs.019422. [DOI] [PubMed] [Google Scholar] · DOI
- [43]Yu Z, et al. The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4. Dev Biol. 2006;299:122–136. doi: 10.1016/j.ydbio.2006.07.015. [DOI] [PubMed] [Google Scholar] · DOI
- [44]Wilanowski T, et al. Perturbed desmosomal cadherin expression in grainy head-like 1-null mice. EMBO J. 2008;27:886–897. doi: 10.1038/emboj.2008.24. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [45]Mehic D, Bakiri L, Ghannadan M, Wagner EF, Tschachler E. Fos and jun proteins are specifically expressed during differentiation of human keratinocytes. J Invest Dermatol. 2005;124:212–220. doi: 10.1111/j.0022-202X.2004.23558.x. [DOI] [PubMed] [Google Scholar] · DOI
- [46]Yates S, Rayner TE. Transcription factor activation in response to cutaneous injury: Role of AP-1 in reepithelialization. Wound Repair Regen. 2002;10:5–15. doi: 10.1046/j.1524-475x.2002.10902.x. [DOI] [PubMed] [Google Scholar] · DOI
- [47]Li G, et al. c-Jun is essential for organization of the epidermal leading edge. Dev Cell. 2003;4:865–877. doi: 10.1016/s1534-5807(03)00159-x. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- [48]Zenz R, Wagner EF. Jun signalling in the epidermis: From developmental defects to psoriasis and skin tumors. Int J Biochem Cell Biol. 2006;38:1043–1049. doi: 10.1016/j.biocel.2005.11.011. [DOI] [PubMed] [Google Scholar] · DOI
- [49]Gazel A, Nijhawan RI, Walsh R, Blumenberg M. Transcriptional profiling defines the roles of ERK and p38 kinases in epidermal keratinocytes. J Cell Physiol. 2008;215:292–308. doi: 10.1002/jcp.21394. [DOI] [PubMed] [Google Scholar] · DOI
- [50]Uv AE, Harrison EJ, Bray SJ. Tissue-specific splicing and functions of the Drosophila transcription factor Grainyhead. Mol Cell Biol. 1997;17:6727–6735. doi: 10.1128/mcb.17.11.6727. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [51]Liaw GJ, et al. The torso response element binds GAGA and NTF-1/Elf-1, and regulates tailless by relief of repression. Genes Dev. 1995;9:3163–3176. doi: 10.1101/gad.9.24.3163. [DOI] [PubMed] [Google Scholar] · DOI
- [52]Ciapponi L, Jackson DB, Mlodzik M, Bohmann D. Drosophila Fos mediates ERK and JNK signals via distinct phosphorylation sites. Genes Dev. 2001;15:1540–1553. doi: 10.1101/gad.886301. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [53]Bosch M, Serras F, Martin-Blanco E, Baguna J. JNK signaling pathway required for wound healing in regenerating Drosophila wing imaginal discs. Dev Biol. 2005;280:73–86. doi: 10.1016/j.ydbio.2005.01.002. [DOI] [PubMed] [Google Scholar] · DOI
- [54]Rubin GM, Spradling AC. Genetic transformation of Drosophila with transposable element vectors. Science. 1982;218:348–353. doi: 10.1126/science.6289436. [DOI] [PubMed] [Google Scholar] · DOI
- [55]Spradling AC, Rubin GM. Transposition of cloned P elements into Drosophila germ line chromosomes. Science. 1982;218:341–347. doi: 10.1126/science.6289435. [DOI] [PubMed] [Google Scholar] · DOI
- [56]Barolo S, Carver LA, Posakony JW. GFP and beta-galactosidase transformation vectors for promoter/enhancer analysis in Drosophila. BioTechniques. 2000;29:726–732. doi: 10.2144/00294bm10. [DOI] [PubMed] [Google Scholar] · DOI
- [57]Barolo S, Castro B, Posakony JW. New Drosophila transgenic reporters: Insulated P-element vectors expressing fast-maturing RFP. Biotechniques. 2004;36:436–442. doi: 10.2144/04363ST03. [DOI] [PubMed] [Google Scholar] · DOI
- [58]Stapleton M, et al. A Drosophila full-length cDNA resource. Genome Biol. 2002;3:RESEARCH0080. doi: 10.1186/gb-2002-3-12-research0080. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [59]Stapleton M, et al. The Drosophila gene collection: Identification of putative full-length cDNAs for 70% of D. melanogaster genes. Genome Res. 2002;12:1294–1300. doi: 10.1101/gr.269102. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [60]Rebeiz M, Posakony JW. GenePalette: A universal software tool for genome sequence visualization and analysis. Dev Biol. 2004;271:431–438. doi: 10.1016/j.ydbio.2004.04.011. [DOI] [PubMed] [Google Scholar] · DOI
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- Authors
- Pearson, J. C., Juarez, M. T., Kim, M., Drivenes, Ø., & McGinnis, W.
- Affiliations
- University of California San Diego (US)
- Section of Cell and Developmental Biology, Division of Biology, University of California at San Diego, La Jolla, CA 92093
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-02-17
- Volume
- 106
- Issue
- 7
- Pages
- 2224-2229
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2630199
- OpenAlex
- W2122277738
- Cited by
- 59
- References
- 1
- Citations by year
- 2025: 2 · 2024: 1 · 2022: 2 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 4 · 2013: 6 · 2012: 7
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Update notices
- correction (2009-11-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM077197, T32GM007240, GM-68524, K12GM068524)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- transcription factor binding sites, enhancer regulation, Drosophila embryo, DDC, PLE, MSN, Fos/Jun, gene regulatory networks
- MeSH terms
- Animals, Binding Sites, Drosophila, Drosophila melanogaster, Enhancer Elements, Genetic, Epidermis, Gene Expression Regulation, Microscopy, Fluorescence, Models, Biological, Models, Genetic, Mutation, Time Factors, Transcription Factors, Transcription, Genetic, Wound Healing
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