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PLOS Biology  2009 

The Atonal Proneural Transcription Factor Links Differentiation and Tumor Formation in Drosophila

DOI: 10.1371/journal.pbio.1000040

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The acquisition of terminal cell fate and onset of differentiation are instructed by cell type–specific master control genes. Loss of differentiation is frequently observed during cancer progression, but the underlying causes and mechanisms remain poorly understood. We tested the hypothesis that master regulators of differentiation may be key regulators of tumor formation. Using loss- and gain-of-function analyses in Drosophila, we describe a critical anti-oncogenic function for the atonal transcription factor in the fly retina, where atonal instructs tissue differentiation. In the tumor context, atonal acts by regulating cell proliferation and death via the JNK stress response pathway. Combined with evidence that atonal's mammalian homolog, ATOH1, is a tumor suppressor gene, our data support a critical, evolutionarily conserved, function for ato in oncogenesis.


[1]  Hassan BA, Bellen HJ (2000) Doing the MATH: is the mouse a good model for fly development? Genes Dev 14: 1852–1865.
[2]  Quan XJ, Hassan BA (2005) From skin to nerve: flies, vertebrates and the first helix. Cell Mol Life Sci 62: 2036–2049.
[3]  Jarman AP, Grau Y, Jan LY, Jan YN (1993) atonal is a proneural gene that directs chordotonal organ formation in the Drosophila peripheral nervous system. Cell 73: 1307–1321.
[4]  Jarman AP, Grell EH, Ackerman L, Jan LY, Jan YN (1994) Atonal is the proneural gene for Drosophila photoreceptors. Nature 369: 398–400.
[5]  Jarman AP, Sun Y, Jan LY, Jan YN (1995) Role of the proneural gene, atonal, in formation of Drosophila chordotonal organs and photoreceptors. Development 121: 2019–2030.
[6]  Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57–70.
[7]  Conheim J (1875) Congenitales, quergestreiftes Muskelsarkon der Nieren. Virchows Arch 65: 64.
[8]  Harris H (2004) Tumor suppression: putting on the brakes. Nature 427: 201.
[9]  Harris H (1985) Suppression of malignancy in hybrid cells: the mechanism. J Cell Sci 79: 83–94.
[10]  Clarke MF, Fuller M (2006) Stem cells and cancer: two faces of eve. Cell 124: 1111–1115.
[11]  Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434: 843–850.
[12]  Roy M, Pear WS, Aster JC (2007) The multifaceted role of Notch in cancer. Curr Opin Genet Dev 17: 52–59.
[13]  Bossuyt W, Kazanjian A, de Geest N, Van Kelst S, De Hertogh G, et al. (2009) Atonal homolog 1 is a tumor suppressor gene. PLoS Biol 7: e1000039. doi:10.1371/journal.pbio.1000039.
[14]  Ferres-Marco D, Gutierrez-Garcia I, Vallejo DM, Bolivar J, Gutierrez-Avi?o FJ, et al. (2006) Epigenetic silencers and Notch collaborate to promote malignant tumors by Rb silencing. Nature 439: 430–436.
[15]  Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, et al. (2007) Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13: 1203–1210.
[16]  John A, Smith ST, Jaynes JB (1995) Inserting the Ftz homeodomain into engrailed creates a dominant transcriptional repressor that specifically turns off Ftz target genes in vivo. Development 121: 1801–1813.
[17]  Domínguez M, Casares F (2005) Organ specification-growth control connection: new in-sights from the Drosophila eye-antennal disc. Dev Dyn 232: 673–684.
[18]  Kurata S, Go MJ, Artavanis-Tsakonas S, Gehring WJ (2000) Notch signaling and the determination of appendage identity. Proc Natl Acad Sci U S A 97: 2117–2122.
[19]  Sukhanova M, Deb DK, Gordon GM, Matakatsu MT, Du W (2007) Proneural bHLH proteins and EGFR signaling coordinately regulate cell type specification and Cdk inhibitor expression during development. Mol Cell Biol 27: 2987–2996.
[20]  Firth LC, Baker NE (2005) Extracellular signals responsible for spatially regulated proliferation in the differentiating Drosophila eye. Dev Cell 8: 541–551.
[21]  Igaki T, Pagliarini RA, Xu T (2006) Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr Biol 16: 1139–1146.
[22]  Uhlirova M, Jasper H, Bohmann D (2005) Non-cell-autonomous induction of tissue overgrowth by JNK/Ras cooperation in a Drosophila tumor model. Proc Natl Acad Sci U S A 102: 13123–13128.
[23]  Wang VY, Hassan BA, Bellen HJ, Zoghbi HY (2002) Drosophila atonal fully rescues the phenotype of Math1 null mice: new functions evolve in new cellular contexts. Curr Biol 12: 1611–1616.
[24]  Hassan BA, Bermingham NA, He Y, Sun Y, Jan YN, et al. (2000) atonal regulates neurite arborization but does not act as a proneural gene in the Drosophila brain. Neuron 25: 549–561.
[25]  Conlon FL, Sedgwick SG, Weston KM, Smith JC (1996) Inhibition of Xbra transcription activation causes defects in mesodermal patterning and reveals autoregulation of Xbra in dorsal mesoderm. Development 122: 2427–2435.
[26]  Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118: 401–415.


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