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Multiple Transcription Factor Codes Activate Epidermal Wound–Response Genes in Drosophila

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Multiple Transcription Factor Codes Activate Epidermal Wound–Response Genes in Drosophila DEVELOPMENTAL BIOLOGY DEVELOPMENTAL BIOLOGY Correction for ‘‘Multiple transcription factor codes activate Correction for ‘‘p75 reduces ␤-amyloid-induced sympathetic epidermal wound–response genes in Drosophila,’’ by Joseph C. innervation deficits in an Alzheimer’s disease mouse model,’’ by Pearson, Michelle T. Juarez, Myungjin Kim, and William Tasha G. Bengoechea, Zhijiang Chen, Deborah O’Leary, Eliezer McGinnis, which appeared in issue 7, February 17, 2009, of Proc Masliah, and Kuo-Fen Lee, which appeared in issue 19, May 12, Natl Acad Sci USA (106:2224–2229; first published January 23, 2009, of Proc Natl Acad Sci USA (106:7870–7875; first published 2009; 10.1073/pnas.0810219106). April 27, 2009; 10.1073/pnas.0901533106). The authors request that Øyvind Drivenes be added to the The authors note that the author name Deborah O’Leary author list between Myungjin Kim and William McGinnis and should have appeared as Debra A. O’Leary. The online version credited with designing research, performing research, contrib- has been corrected. The corrected author line and author uting new reagents/analytic tools, and analyzing data. The online contribution footnote appear below. version has been corrected. The corrected author and affiliation lines, author contributions, and related footnotes appear below. Tasha G. Bengoechea, Zhijiang Chen, Debra A. O’Leary, Eliezer Masliah, and Kuo-Fen Lee Joseph C. Pearson1, Michelle T. Juarez, Myungjin Kim, 2 3 Author contributions: T.G.B., Z.C., and D.A.O. designed research; T.G.B., Z.C., and D.A.O. Øyvind Drivenes , and William McGinnis performed research; E.M. contributed new reagents/analytic tools; T.G.B., Z.C., and D.A.O. analyzed data; and T.G.B., Z.C., and K.-F.L. wrote the paper. Section of Cell and Developmental Biology, Division of Biology, University of California at San Diego, La Jolla, CA 92093 www.pnas.org/cgi/doi/10.1073/pnas.0912235106 Author contributions: J.C.P., M.T.J., M.K., Ø.D., and W.M. designed research; J.C.P., M.T.J., M.K., and Ø.D. performed research; Ø.D. contributed new reagents/analytic tools; J.C.P., M.T.J., M.K., Ø.D., and W.M. analyzed data; and J.C.P. and W.M. wrote the paper. 1Present address: Program in Molecular Biology and Biotechnology, University of North Carolina, Chapel Hill, NC 27599. 2Present address: Institute of Marine Research, P.O. Box 1870 Nordnes, 5817 Bergen, Norway. 3To whom correspondence should be addressed. E-mail: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.0912436106 20134 ͉ www.pnas.org Downloaded by guest on September 28, 2021 Multiple transcription factor codes activate epidermal wound–response genes in Drosophila Joseph C. Pearson1, Michelle T. Juarez, Myungjin Kim, and William McGinnis2 Section of Cell and Developmental Biology, Division of Biology, University of California at San Diego, La Jolla, CA 92093 Edited by Kathryn V. Anderson, Sloan–Kettering Institute, New York, NY, and approved December 5, 2008 (received for review October 14, 2008) Wounds in Drosophila and mouse embryos induce similar genetic (kkv) and misshapen (msn). Ddc, ple, kkv, and msn are all pathways to repair epidermal barriers. However, the transcription transcriptionally activated within minutes after epidermal factors that transduce wound signals to repair epidermal barriers are wounding. Three of the genes use overlapping transcriptional largely unknown. We characterize the transcriptional regulatory codes involving GRH and FOS to activate their epidermal enhancers of 4 genes—Ddc, ple, msn, and kkv—that are rapidly wound enhancers, but kkv uses a fundamentally different code activated in epidermal cells surrounding wounds in late Drosophila for wound activation. Whereas the common wound–response embryos and early larvae. These epidermal wound enhancers all cis-regulatory codes we describe will be useful in the identifica- contain evolutionarily conserved sequences matching binding sites tion of new epidermal wound enhancers in both vertebrates and for JUN/FOS and GRH transcription factors, but vary widely in trans- invertebrates, the evidence for alternative wound–response and cis-requirements for these inputs and their binding sites. We codes provides insight into how genetic control of wound healing propose that the combination of GRH and FOS is part of an ancient has evolved in metazoans. wound–response pathway still used in vertebrates and invertebrates, but that other mechanisms have evolved that result in similar tran- Results scriptional output. A common, but largely untested assumption of Minimal Ddc Epidermal Wound Enhancers. By using reporter gene bioinformatic analyses of gene regulatory networks is that transcrip- constructs in Drosophila embryos, we previously identified a tion units activated in the same spatial and temporal patterns will 0.47-kb DNA fragment just upstream of the Ddc gene that require the same cis-regulatory codes. Our results indicate that this is functioned as an epidermal wound enhancer in late embryos BIOLOGY an overly simplistic view. (Fig. 1A) (11). This enhancer can activate GFP reporter expres- DEVELOPMENTAL sion in a zone around aseptic epidermal punctures in late cuticle ͉ grainy head ͉ fos ͉ wound repair embryos (Fig. 1B), in larvae just before molts (data not shown), and in very young adults (Fig. 1C). The Ddc .47 wound-enhancer nimals have evolved systems to sense and repair epidermal DNA contains 2 regions upstream of the basal promoter that are Awounds and to fight microbial infections that follow wound- highly conserved among all sequenced drosophilid species: CR1 ing. Many wound responses are carried out by homologous (44 nt) and CR2 (13 nt) (Fig. 1A and SI Appendix). The CR2 genetic pathways in arthropods and vertebrates and thus appar- sequence consists largely of a high-affinity GRH binding site (ACCGGTT) (12, 19, 20), which is required for wound-enhancer ently had evolved in a common ancestor of bilateral animals. function (11). Ddc .47 CR1 contains a sequence matching the These responses include pathways mediating reepithelialization consensus binding site (TGANTCA) for AP-1, a transcription (1–9), responses to microbial invasion (10), and regeneration of factor consisting of a JUN-FOS dimer (21). epidermal barrier layers (11, 12). The outermost epidermal To test for AP-1-like site function in the Ddc .47 wound barrier in mammals is the stratum corneum, a constantly regen- enhancer, we mutated the conserved AP-1-like site in CR1 and erated layer of crosslinked keratinocytes, proteins, and lipids a second AP-1-like site that lies between CR1 and CR2 (Fig. 1A). (13). The analogous protective barrier for arthropods is the This construct is unable to activate reporter expression after cuticle, comprised of crosslinked chitin, proteins, and lipids (14). wounding (Fig. 1D). We also deleted 355 bp between the conserved Although mammalian and arthropodal epidermal barriers are regions (Ddc Gap) (Fig. 1A), to test whether any required DNA constructed in largely different ways, they share a homologous elements are located within the region between CR1 and CR2. This genetic pathway controlling barrier repair that involves tran- deletion mutant functions as an epidermal wound enhancer, but the scription factors of the Grainy head (GRH) family (11, 12). number of cells that activate reporter gene expression is reduced One central question in the control of epidermal wound repair compared with WT Ddc .47 (Fig. 1E). In summary, both AP-1-like is how signals are integrated at the level of transcription to and GRH consensus sequences are absolutely required for Ddc .47 activate the large battery of effector genes that mediate wound wound activation, and a minimal enhancer of 117 bp containing responses. Although many genes are known to be activated in these sites is sufficient for modest activation in cells around wound epidermal cells after wounding (15–17), little is known about the sites. However, additional sequences within .47 Ddc contribute to cis-regulatory enhancers that mediate wound-induced gene ac- the strength of this epidermal wound enhancer. tivation. In Drosophila, there are only a few known genes activated at epidermal wound sites (11, 14, 17). Two of these genes encode the enzymes Dopa decarboxylase (Ddc) and Author contributions: J.C.P., M.T.J., M.K., and W.M. designed research; J.C.P., M.T.J., and Tyrosine hydroxylase (encoded by ple) (11). These 2 enzymes are M.K. performed research; J.C.P., M.T.J., M.K., and W.M. analyzed data; and J.C.P. and W.M. limiting steps in the pathway to produce the highly reactive wrote the paper. quinones that crosslink chitin and cuticle proteins during the The authors declare no conflict of interest. construction and repair of cuticular barriers (18). This article is a PNAS Direct Submission. To better characterize the transcriptional wound response in Freely available online through the PNAS open access option. Drosophila embryos, we have mutagenized minimal Ddc and ple 1Present address: Program in Molecular Biology and Biotechnology, University of North epidermal wound enhancers, showing that both require AP-1- Carolina, Chapel Hill, NC 27599. like and GRH consensus sites. We then searched for AP-1 and 2To whom correspondence should be addressed. E-mail: [email protected]. GRH consensus binding sites in the regulatory DNA for other This article contains supporting information online at www.pnas.org/cgi/content/full/ epidermal wound–response genes, which led to the identification 0810219106/DCSupplemental. of epidermal wound enhancers for the genes krotzkopf verkehrt © 2009 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0810219106 PNAS Early Edition ͉ 1of6 -4.14 kb CR1 CR2 -3. A A 45 kb WR WR Ddc .47 + ple-WE1 + Ddc .47 APm - ple-WE1 APm - Ddc .47 GRHm - ple-WE1 GRHm +/- ple-WE1 CREBm + Ddc Gap +/- ple-WE1 EXDm + Ddc .47 embryo B C Ddc .47 adult ple-WE1 HOXm + ple-WE1 APm APc - TGANTCA B C CREBc - TGACGTMA EXDc - WGATTGAW GRHc - ACYNGTT HOXc - YMATTA D GRHm EGCREBmF EXDm HOXm D Ddc .47 APm E Ddc Gap Fig.
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