Gradients of cell signaling molecules and regulatoryfactorsare pervasivelyused in a variety of patterning process in metazoan development. Examples include the Sonic Hedgehog gradient that specifies different neuronal cell types in the neural tube of vertebrateembryos,and the Dpp gradient that patterns the developing wing imaginal disk in Drosophila larvae. The Toll-Dorsal signaling pathway represents one of the most thoroughly characterized gradient systemsin animal development. The proposed study represents a continuationof our efforts to determine how the Dorsal regulatorygradient produces multiple thresholds of gene expression and tissue differentiation in the early Drosophila embryo. The research plan includes 3 specific aims, First, we will examine the activitiesof Dorsal target genes that were identified in recent whole-genome microarray assays. Among the newly identified genes that will be tested is Eiger, the major TNF homolog in the Drosophila genome, and Mes4, which encodes a tissue-specific subunit of the CACAAT-box binding protein complex, NF-Y. Second, we will use a combination of bioinformatics methods and transgenic assays to determine how the Dorsal gradient regulates the expression of different target genes in a concentration-dependent manner. Particular efforts will focus on defining a"cis- regulatory code", whereby coordinately regulated target enhancers share a characteristic combination of factor binding sites, including binding sites for Dorsal and additional,mainlyunknown regulatory factors. Third, we will determine whether immunity genes that are induced upon infection or injury share a similar organization of cis-regulatory elements. Particular efforts will focus on genes that are activated by the Dorsal-related immunity genes, Dif and Relish, and the GATA transcriptionfactor, Serpent.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Hoodbhoy, Tanya
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University of California Berkeley
Schools of Arts and Sciences
United States
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Levine, Michael; Cattoglio, Claudia; Tjian, Robert (2014) Looping back to leap forward: transcription enters a new era. Cell 157:13-25
Boettiger, Alistair Nicol; Levine, Michael (2013) Rapid transcription fosters coordinate snail expression in the Drosophila embryo. Cell Rep 3:8-15
Lagha, Mounia; Bothma, Jacques P; Esposito, Emilia et al. (2013) Paused Pol II coordinates tissue morphogenesis in the Drosophila embryo. Cell 153:976-87
Papatsenko, Dmitri; Levine, Michael (2011) The Drosophila gap gene network is composed of two parallel toggle switches. PLoS One 6:e21145
Papatsenko, Dmitri; Levine, Michael; Goltsev, Yury (2011) Clusters of temporal discordances reveal distinct embryonic patterning mechanisms in Drosophila and anopheles. PLoS Biol 9:e1000584
Perry, Michael W; Boettiger, Alistair N; Bothma, Jacques P et al. (2010) Shadow enhancers foster robustness of Drosophila gastrulation. Curr Biol 20:1562-7
Perry, M W; Cande, J D; Boettiger, A N et al. (2009) Evolution of insect dorsoventral patterning mechanisms. Cold Spring Harb Symp Quant Biol 74:275-9
Papatsenko, Dmitri (2009) Stripe formation in the early fly embryo: principles, models, and networks. Bioessays 31:1172-80
Cande, Jessica Doran; Chopra, Vivek S; Levine, Michael (2009) Evolving enhancer-promoter interactions within the tinman complex of the flour beetle, Tribolium castaneum. Development 136:3153-60
Goltsev, Yury; Rezende, Gustavo L; Vranizan, Karen et al. (2009) Developmental and evolutionary basis for drought tolerance of the Anopheles gambiae embryo. Dev Biol 330:462-70

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