Epithelial sheet spreading and fusion underlie important developmental processes. Well-characterized examples of such epithelial morphogenetic events have been provided by studies in Drosophila, and include embryonic dorsal closure, formation of the adult thorax and wound healing. All of these processes require the basic region-leucine zipper (bZIP) transcription factors Jun and Fos. Much less is known about morphogenesis of the fly abdomen, which involves replacement of larval epidermal cells (LECs) with adult histoblasts that divide, migrate and finally fuse to form the adult epidermis during metamorphosis. Here, we implicate Drosophila Activating transcription factor 3 (Atf3), the single ortholog of human ATF3 and JDP2 bZIP proteins, in abdominal morphogenesis. During the process of the epithelial cell replacement, transcription of the atf3 gene declines. When this downregulation is experimentally prevented, the affected LECs accumulate cell-adhesion proteins and their extrusion and replacement with histoblasts are blocked. The abnormally adhering LECs consequently obstruct the closure of the adult abdominal epithelium. This closure defect can be either mimicked and further enhanced by knockdown of the small GTPase Rho1 or, conversely, alleviated by stimulating ecdysone steroid hormone signaling. Both Rho and ecdysone pathways have been previously identified as effectors of the LEC replacement. To elicit the gain-of-function effect, Atf3 specifically requires its binding partner Jun. Our data thus identify Atf3 as a new functional partner of Drosophila Jun during development.

Biology Center Czech Academy of Sciences and Department of Molecular Biology University of South Bohemia Ceske Budejovice 37005 Czech Republic

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Allan A. L., Albanese C., Pestell R. G., LaMarre J. (2001). Activating transcription factor 3 induces DNA synthesis and expression of cyclin D1 in hepatocytes. J. Biol. Chem. 276, 27272-27280 PubMed

Aronheim A., Zandi E., Hennemann H., Elledge S. J., Karin M. (1997). Isolation of an AP-1 repressor by a novel method for detecting protein-protein interactions. Mol. Cell. Biol. 17, 3094-3102 PubMed PMC

Bayer C. A., Halsell S. R., Fristrom J. W., Kiehart D. P., von Kalm L. (2003). Genetic interactions between the RhoA and Stubble-stubbloid loci suggest a role for a type II transmembrane serine protease in intracellular signaling during Drosophila imaginal disc morphogenesis. Genetics 165, 1417-1432 PubMed PMC

Bischoff M., Cseresnyes Z. (2009). Cell rearrangements, cell divisions and cell death in a migrating epithelial sheet in the abdomen of Drosophila. Development 136, 2403-2411 PubMed PMC

Bohmann D., Ellis M. C., Staszewski L. M., Mlodzik M. (1994).. Drosophila Jun mediates Ras-dependent photoreceptor determination. Cell 78, 973-986 PubMed

Chu H. M., Tan Y., Kobierski L. A., Balsam L. B., Comb M. J. (1994). Activating transcription factor-3 stimulates 3′,5′-cyclic adenosine monophosphate-dependent gene expression. Mol. Endocrinol. 8, 59-68 PubMed

Ciapponi L., Jackson D. B., Mlodzik M., Bohmann D. (2001). Drosophila Fos mediates ERK and JNK signals via distinct phosphorylation sites. Genes Dev. 15, 1540-1553 PubMed PMC

Colombani J., Raisin S., Pantalacci S., Radimerski T., Montagne J., Leopold P. (2003). A nutrient sensor mechanism controls Drosophila growth. Cell 114, 739-749 PubMed

Duguay D., Foty R. A., Steinberg M. S. (2003). Cadherin-mediated cell adhesion and tissue segregation: qualitative and quantitative determinants. Dev. Biol. 253, 309-323 PubMed

Eresh S., Riese J., Jackson D. B., Bohmann D., Bienz M. (1997). A CREB-binding site as a target for decapentaplegic signalling during Drosophila endoderm induction. EMBO J. 16, 2014-2022 PubMed PMC

Fassler J., Landsman D., Acharya A., Moll J. R., Bonovich M., Vinson C. (2002). B-ZIP proteins encoded by the Drosophila genome: evaluation of potential dimerization partners. Genome Res. 12, 1190-1200 PubMed PMC

Fawcett T. W., Martindale J. L., Guyton K. Z., Hai T., Holbrook N. J. (1999). Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem. J. 339, 135-141 PubMed PMC

Gaziova I., Bonnette P. C., Henrich V. C., Jindra M. (2004). Cell-autonomous roles of the ecdysoneless gene in Drosophila development and oogenesis. Development 131, 2715-2725 PubMed

Gilchrist M., Thorsson V., Li B., Rust A. G., Korb M., Roach J. C., Kennedy K., Hai T., Bolouri H., Aderem A. (2006). Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 441, 173-178 PubMed

Giot L., Bader J. S., Brouwer C., Chaudhuri A., Kuang B., Li Y., Hao Y. L., Ooi C. E., Godwin B., Vitols E., et al. (2003). A protein interaction map of Drosophila melanogaster. Science 302, 1727-1736 PubMed

Hai T., Curran T. (1991). Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc. Natl. Acad. Sci. USA 88, 3720-3724 PubMed PMC

Hai T. W., Liu F., Coukos W. J., Green M. R. (1989). Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers. Genes Dev. 3, 2083-2090 PubMed

Harrison D. A., Binari R., Nahreini T. S., Gilman M., Perrimon N. (1995). Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. EMBO J. 14, 2857-2865 PubMed PMC

Hartman M. G., Lu D., Kim M. L., Kociba G. J., Shukri T., Buteau J., Wang X., Frankel W. L., Guttridge D., Prentki M., et al. (2004). Role for activating transcription factor 3 in stress-induced beta-cell apoptosis. Mol. Cell. Biol. 24, 5721-5732 PubMed PMC

Hayashi S., Hirose S., Metcalfe T., Shirras A. D. (1993). Control of imaginal cell development by the escargot gene of Drosophila. Development 118, 105-115 PubMed

Heinrich R., Livne E., Ben-Izhak O., Aronheim A. (2004). The c-Jun dimerization protein 2 inhibits cell transformation and acts as a tumor suppressor gene. J. Biol. Chem. 279, 5708-5715 PubMed

Hou X. S., Goldstein E. S., Perrimon N. (1997). Drosophila Jun relays the Jun amino-terminal kinase signal transduction pathway to the Decapentaplegic signal transduction pathway in regulating epithelial cell sheet movement. Genes Dev. 11, 1728-1737 PubMed

Hsu J. C., Laz T., Mohn K. L., Taub R. (1991). Identification of LRF-1, a leucine-zipper protein that is rapidly and highly induced in regenerating liver. Proc. Natl. Acad. Sci. USA 88, 3511-3515 PubMed PMC

Hsu J. C., Bravo R., Taub R. (1992). Interactions among LRF-1, JunB, c-Jun, and c-Fos define a regulatory program in the G1 phase of liver regeneration. Mol. Cell. Biol. 12, 4654-4665 PubMed PMC

Hyun J., Becam I., Yanicostas C., Bohmann D. (2006). Control of G2/M transition by Drosophila Fos. Mol. Cell. Biol. 26, 8293-8302 PubMed PMC

Ishiguro T., Nagawa H. (2001). ATF3 gene regulates cell form and migration potential of HT29 colon cancer cells. Oncol. Res. 12, 343-346 PubMed

Iyengar P., Combs T. P., Shah S. J., Gouon-Evans V., Pollard J. W., Albanese C., Flanagan L., Tenniswood M. P., Guha C., Lisanti M. P., et al. (2003). Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene 22, 6408-6423 PubMed

Jin C., Li H., Murata T., Sun K., Horikoshi M., Chiu R., Yokoyama K. K. (2002). JDP2, a repressor of AP-1, recruits a histone deacetylase 3 complex to inhibit the retinoic acid-induced differentiation of F9 cells. Mol. Cell. Biol. 22, 4815-4826 PubMed PMC

Jindra M., Gaziova I., Uhlirova M., Okabe M., Hiromi Y., Hirose S. (2004). Coactivator MBF1 preserves the redox-dependent AP-1 activity during oxidative stress in Drosophila. EMBO J. 23, 3538-3547 PubMed PMC

Kawauchi J., Zhang C., Nobori K., Hashimoto Y., Adachi M. T., Noda A., Sunamori M., Kitajima S. (2002). Transcriptional repressor activating transcription factor 3 protects human umbilical vein endothelial cells from tumor necrosis factor-alpha-induced apoptosis through down-regulation of p53 transcription. J. Biol. Chem. 277, 39025-39034 PubMed

Kiehart D. P., Galbraith C. G., Edwards K. A., Rickoll W. L., Montague R. A. (2000). Multiple forces contribute to cell sheet morphogenesis for dorsal closure in Drosophila. J. Cell Biol. 149, 471-490 PubMed PMC

Kockel L., Zeitlinger J., Staszewski L. M., Mlodzik M., Bohmann D. (1997). Jun in Drosophila development: redundant and non-redundant functions, and regulation by two MAPK signal transduction pathways. Genes Dev. 11, 1748-1758 PubMed

Kockel L., Homsy J. G., Bohmann D. (2001). Drosophila AP-1: lessons from an invertebrate. Oncogene 20, 2347-2364 PubMed

Lu D., Wolfgang C. D., Hai T. (2006). Activating transcription factor 3, a stress-inducible gene, suppresses Ras-stimulated tumorigenesis. J. Biol. Chem. 281, 10473-10481 PubMed

Madhavan M. M., Madhavan K. (1980). Morphogenesis of the epidermis of adult abdomen of Drosophila. J. Embryol. Exp. Morphol. 60, 1-31 PubMed

Madhavan M. M., Schneiderman H. A. (1977). Histological analysis of the dynamics of growth of imaginal discs and histoblast nests during the larval development of Drosophila melanogaster. Wilhem Roux' Arch. Dev. Biol. 183, 269-305 PubMed

Mashima T., Udagawa S., Tsuruo T. (2001). Involvement of transcriptional repressor ATF3 in acceleration of caspase protease activation during DNA damaging agent-induced apoptosis. J. Cell. Physiol. 188, 352-358 PubMed

Montminy M. R., Sevarino K. A., Wagner J. A., Mandel G., Goodman R. H. (1986). Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc. Natl. Acad. Sci. USA 83, 6682-6686 PubMed PMC

Muro I., Berry D. L., Huh J. R., Chen C. H., Huang H., Yoo S. J., Guo M., Baehrecke E. H., Hay B. A. (2006). The Drosophila caspase Ice is important for many apoptotic cell deaths and for spermatid individualization, a nonapoptotic process. Development 133, 3305-3315 PubMed

Nakade K., Pan J., Yoshiki A., Ugai H., Kimura M., Liu B., Li H., Obata Y., Iwama M., Itohara S., et al. (2007). JDP2 suppresses adipocyte differentiation by regulating histone acetylation. Cell Death Differ. 14, 1398-1405 PubMed

Nakagomi S., Suzuki Y., Namikawa K., Kiryu-Seo S., Kiyama H. (2003). Expression of the activating transcription factor 3 prevents c-Jun N-terminal kinase-induced neuronal death by promoting heat shock protein 27 expression and Akt activation. J. Neurosci. 23, 5187-5196 PubMed PMC

Ninov N., Chiarelli D. A., Martin-Blanco E. (2007). Extrinsic and intrinsic mechanisms directing epithelial cell sheet replacement during Drosophila metamorphosis. Development 134, 367-379 PubMed

Ninov N., Manjon C., Martin-Blanco E. (2009). Dynamic control of cell cycle and growth coupling by ecdysone, EGFR, and PI3K signaling in Drosophila histoblasts. PLoS Biol. 7, E1000079 PubMed PMC

Nobori K., Ito H., Tamamori-Adachi M., Adachi S., Ono Y., Kawauchi J., Kitajima S., Marumo F., Isobe M. (2002). ATF3 inhibits doxorubicin-induced apoptosis in cardiac myocytes: a novel cardioprotective role of ATF3. J. Mol. Cell. Cardiol. 34, 1387-1397 PubMed

Oda H., Tsukita S. (2001). Real-time imaging of cell-cell adherens junctions reveals that Drosophila mesoderm invagination begins with two phases of apical constriction of cells. J. Cell Sci. 114, 493-501 PubMed

Ostrovsky O., Bengal E., Aronheim A. (2002). Induction of terminal differentiation by the c-Jun dimerization protein JDP2 in C2 myoblasts and rhabdomyosarcoma cells. J. Biol. Chem. 277, 40043-40054 PubMed

Perkins K. K., Admon A., Patel N., Tjian R. (1990). The Drosophila Fos-related AP-1 protein is a developmentally regulated transcription factor. Genes Dev. 4, 822-834 PubMed

Perkins K. K., Dailey G. M., Tjian R. (1988). Novel Jun- and Fos-related proteins in Drosophila are functionally homologous to enhancer factor AP-1. EMBO J. 7, 4265-4273 PubMed PMC

Piu F., Aronheim A., Katz S., Karin M. (2001). AP-1 repressor protein JDP-2: inhibition of UV-mediated apoptosis through p53 down-regulation. Mol. Cell. Biol. 21, 3012-3024 PubMed PMC

Qi L., Saberi M., Zmuda E., Wang Y., Altarejos J., Zhang X., Dentin R., Hedrick S., Bandyopadhyay G., Hai T., et al. (2009). Adipocyte CREB promotes insulin resistance in obesity. Cell Metab. 9, 277-286 PubMed PMC

Riesgo-Escovar J. R., Hafen E. (1997). Common and distinct roles of DFos and DJun during Drosophila development. Science 278, 669-672 PubMed

Rosenberger C. M., Clark A. E., Treuting P. M., Johnson C. D., Aderem A. (2008). ATF3 regulates MCMV infection in mice by modulating IFN-gamma expression in natural killer cells. Proc. Natl. Acad. Sci. USA 105, 2544-2549 PubMed PMC

Tamura K., Hua B., Adachi S., Guney I., Kawauchi J., Morioka M., Tamamori-Adachi M., Tanaka Y., Nakabeppu Y., Sunamori M., et al. (2005). Stress response gene ATF3 is a target of c-myc in serum-induced cell proliferation. EMBO J. 24, 2590-2601 PubMed PMC

Tautz D., Pfeifle C. (1989). A non-radioactive in situ hybridization method for the localization of specific RNAs in Drosophila embryos reveals translational control of the segmentation gene hunchback. Chromosoma 98, 81-85 PubMed

Ward R. E., Evans J., Thummel C. S. (2003). Genetic modifier screens in Drosophila demonstrate a role for Rho1 signaling in ecdysone-triggered imaginal disc morphogenesis. Genetics 165, 1397-1415 PubMed PMC

Xia Y., Karin M. (2004). The control of cell motility and epithelial morphogenesis by Jun kinases. Trends Cell Biol. 14, 94-101 PubMed

Yin X., Dewille J. W., Hai T. (2008). A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. Oncogene 27, 2118-2127 PubMed

Zeitlinger J., Bohmann D. (1999). Thorax closure in Drosophila: involvement of Fos and the JNK pathway. Development 126, 3947-3956 PubMed

Zeitlinger J., Kockel L., Peverali F. A., Jackson D. B., Mlodzik M., Bohmann D. (1997). Defective dorsal closure and loss of epidermal decapentaplegic expression in Drosophila fos mutants. EMBO J. 16, 7393-7401 PubMed PMC

Atf3 links loss of epithelial polarity to defects in cell differentiation and cytoarchitecture