Dorsoventral patterning of the Drosophila embryo is controlled by a maternal regulatory factor, dorsal (dl), which is a member of the Rel family of transcription factors. A gradient of dl protein initiates the differentiation of three basic embryonic tissues during early development: mesoderm, and dorsal ectoderm. This gradient is probably established by the differential activation of a signal transduction pathway that is closely related to mammalian cytokine pathways. An analysis of this process should provide general insights regarding how differential activation of a ligand-receptor signaling pathway elicits distinct responses in cell differentiation and proliferation. The mechanism by which dl sets different thresholds of tissue differentiation has been investigated by analyzing the regulation of target genes that are directly regulated by different concentrations of dl protein. These studies reveal that occupancy of dl binding sites in target promoters determines the corsoventral limits of gene expression in response to the dl gradient. Occupancy is dictated by the intrinsic affinities of dl binding sites, and by cooperative DNA binding interactions between dl and ubiquitously expressed helix-loop-helix (HLH) proteins. For example, target promoters containing both high affinity dl binding sites and closely linked E box sequences are activated in ventral and lateral regions (the presumptive mesoderm and neuroectoderm) in response to both high and low levels of dl. Localized expression in the lateral neuroectoderm is achieved through transcriptional repression by snail, a zinc finger protein that is regulated by dl and restricted to the presumptive mesoderm in ventral regions. The current proposal represents a continuation of our efforts to determine how dl controls embryonic development. Many of the proposed experiments will exploit the unique advantages of the Drosophila embryo as an assay system for analyzing basic aspects of gene regulation. The research plan includes 4 specific aims: i) determine how the zinc finger protein snail mediates transcriptional repression; ii) determine how dl functions as a transcription activator and repressor, including an analysis of dl-TBP (TATA binding protein) and dl-corepressor interactions; iii) analyze the modulation of identified transcription factors by signaling pathways, including a determination of how dl-mediated repression is selectively blocked by the torso receptor tyrosine kinase signaling pathway, and an analysis of interactions dpp (TGF-beta) and the homeodomain protein zerknullt (zen); and, iv) investigate the role of growth factors in the subdivision of the embryonic mesoderm into somatic and visceral lineages.
| Lim, Bomyi; Levine, Michael; Yamazaki, Yuji (2017) Transcriptional Pre-patterning of Drosophila Gastrulation. Curr Biol 27:286-290 |
| Esposito, Emilia; Lim, Bomyi; Guessous, Ghita et al. (2016) Mitosis-associated repression in development. Genes Dev 30:1503-8 |
| Fukaya, Takashi; Lim, Bomyi; Levine, Michael (2016) Enhancer Control of Transcriptional Bursting. Cell 166:358-368 |
| Farley, Emma K; Olson, Katrina M; Zhang, Wei et al. (2015) Suboptimization of developmental enhancers. Science 350:325-8 |
| Farley, Emma K; Olson, Katrina M; Levine, Michael S (2015) Regulatory Principles Governing Tissue Specificity of Developmental Enhancers. Cold Spring Harb Symp Quant Biol 80:27-32 |
| Levine, Michael; Cattoglio, Claudia; Tjian, Robert (2014) Looping back to leap forward: transcription enters a new era. Cell 157:13-25 |
| Levine, Michael (2014) The contraction of time and space in remote chromosomal interactions. Cell 158:243-244 |
| 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 |
| Lagha, Mounia; Bothma, Jacques P; Levine, Michael (2012) Mechanisms of transcriptional precision in animal development. Trends Genet 28:409-16 |
Showing the most recent 10 out of 78 publications
