Gerardo Jiménez: Gene expression and signaling
During animal development, the differentiation of cells, tissues and organs is tightly regulated through specific gene expression programs. Our group is particularly interested in studying the transcriptional and cell signaling mechanisms responsible for this control. Using Drosophila as a model system, we have been dissecting the activities of repressor and co-repressor factors, as well as the responses induced by receptor tyrosine kinase (RTK) pathways during pattern formation and differentiation. One emerging theme has been the identification of the Capicua transcriptional repressor as a general sensor targeted by multiple RTK-initiated signals. Because the molecules and pathways that we study are conserved in evolution, our results have direct implications for human biology and disease.
A focus of our lab is is to understand how RTK signaling pathways regulate transcriptional and developmental responses. RTKs often signal through the Ras-MAPK pathway, which ultimately affects nuclear gene expression by phosphorylating specific transcription factors. Among the best characterized targets of Ras-MAPK signaling are the c-Fos, Myc and ETS family proteins, all of which play critical functions in the cell.
We have been studying the HMG-box protein Capicua (Cic) as a novel general sensor of RTK signaling. We identified Cic because of its role in Drosophila embryogenesis downstream of the Torso RTK pathway, but subsequent analyses have shown that Cic acts downstream of multiple RTK signals during fly development. In general, Cic represses transcription of RTK-responsive genes in unstimulated cells and tissues, whereas RTK signaling inhibits Cic activity and this allows expression of its target genes. Importantly, Cic is similarly regulated by RTK signaling in mammals and has been implicated in human neurodegeneration and in various forms of cancer, where it behaves as a tumor and metastasis suppressor.
Another main interest concerns the mechanisms controlling body pattern formation in Drosophila. In one project we have studied the mechanisms that initiate dorsoventral (DV) axis formation during oogenesis. As part of this work, we have identified a transcriptional circuit linking EGFR activation to localized repression of pipe, a gene that signals the induction of ventral fates.
We are also characterizing the activities of different repressor and corepressor proteins such as Tailless, Atrophin and Groucho, which play important roles in early embryonic patterning and are also involved in human pathologies.
- Forés, M., Papagianni, A., Rodríguez-Muñoz, L. and Jiménez, G. (2017) Using CRISPR-Cas9 to study ERK signaling in Drosophila. Methods Mol. Biol. 1487, 353-365.
- Yang, L., Paul, S., Trieu, K.G., Dent, L.G., Froldi, F., Forés, M., Webster, K., Siegfried, K.R., Kondo, S. Harvey, K., Cheng, L., Jiménez, G., Shvartsman, S. Y. and Veraksa, A. (2016) Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua. Proc. Natl. Acad. Sci. USA 113, 10583-10588.
- Samee, Md. A. H., Lim, B., Samper, N., Lu, H., Rushlow, C. A., Jiménez, G., Shvartsman, S. Y. and Sinha, S. (2015) A systematic ensemble approach to thermodynamic modeling of gene expression from sequence data. Cell Systems 1, 396-407.
- Jin, Y., Ha, N., Forés, M., Xiang, J., Glaßër, C., Maldera, J., Jiménez, G. and Edgar, B. A. (2015) EGFR/Ras signaling controls Drosophila intestinal stem cell proliferation via Capicua-regulated genes. PLOS Genetics 11, e1005634.
- Forés, M., Ajuria, L., Samper, N., Astigarraga, S., Nieva, C., Grossman, R., González-Crespo, S., Paroush, Z. and Jiménez, G. (2015) Origins of context-dependent gene repression by Capicua. PLOS Genetics 11, e1004902.
- Lim, B., Samper, N., Lu, H., Rushlow, C., Jiménez*, G. and Shvartsman*, S. Y. (2013) Kinetics of gene derepression by ERK signaling. Proc. Natl. Acad. Sci. USA 110, 10330-10335. (*Corresponding authors).
- Andreu, M. J., Ajuria, L., Samper, N., González-Pérez, E., Campuzano, S., González-Crespo, S. and Jiménez, G. (2012) EGFR-dependent downregulation of Capicua and the establishment of Drosophila dorsoventral polarity. Fly (Austin) 6, 234-239.
- Helman, A., Lim, B., Andreu, M. J., Kim, Y., Shestkin, T., Lu, H., Jiménez, G., Shvartsman, S. Y. and Paroush, Z. (2012) RTK signaling modulates the Dorsal gradient. Development 139, 3032-3039.
- Andreu, M. J., González-Pérez, E., Ajuria, L., Samper, N., González-Crespo, S., Campuzano, S. and Jiménez, G. (2012) Mirror represses pipe expression in follicle cells to initiate dorsoventral axis formation in Drosophila. Development 139, 1110-1114.
- Jiménez, G. Shvartsman S. and Paroush, Z. (2012) The Capicua repressor - a general sensor of RTK signaling in development and disease. J. Cell Sci. 125, 1383-1391.
- Ajuria, L., Nieva, C., Winkler, C., Kuo, D., Samper, N., Andreu, M. J., Helman, A., González-Crespo, S., Paroush, Z., Courey, A. J. and Jiménez, G. (2011) Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila. Development 138, 915-924.
- Kim, Y., Andreu, M. J., Lim, B., Chung, K., Terayama, M., Jiménez, G., Berg, C. A., Lu, H. and Shvartsman, S. Y. (2011) Gene regulation by MAPK substrate competition. Dev. Cell 20, 880-887.
- Helman, A., Cinnamon, E., Mezuman, S., Hayouka, Z., von Ohlen, T., Orian, A., Jiménez, G. and Paroush, Z. (2011) Phosphorylation of Groucho mediates RTK feddback inhibition and prolonged pathway target gene expression. Curr. Biol.21, 1102-1110.
- Kim, Y., Paroush, Z., Nairz, K., Hafen, E., Jiménez*, G. and Shvartsman*, S. Y. (2011) Substrate-dependent control of MAPK phosphorylation in vivo. Mol. Syst. Biol. 7, article number 467.
- Kim, Y., Coppey, M., Grosman, R., Ajuria, L., Jiménez, G., Paroush, Z. and Shvartsman, S. Y. (2010) MAPK substrate competition integrates patterning signals in the Drosophila embryo. Curr. Biol. 20, 446-451.
- Cinnamon, E., Helman, R., Ben-Haroush Schyr, R., Orian, A., Jiménez, G. and Paroush, Z. (2008) Multiple RTK pathways down-regulate Groucho-mediated repression in Drosophila embryogenesis. Development 135, 829-837.
- Astigarraga, S., Grossman, R., Díaz-Delfín, J., Caelles, C., Paroush, Z. and Jiménez, G. (2007) A MAPK docking site is critical for downregulation of Capicua by Torso and EGFR RTK signaling. EMBO J. 26, 668-677.
- Morán, E. and Jiménez, G. (2006) The Tailless nuclear receptor acts as a dedicated repressor in the early Drosophila embryo. Mol. Cell. Biol. 26, 3446-3454.
- Cinnamon, E., Gur-Wahnon, D., Helman, A., St Johnston, D., Jiménez, G and Paroush, Z. (2004) Capicua integrates input from two maternal systems in Drosophila terminal patterning. EMBO J. 23, 4571-4582.
- Previous publications
- Jiménez, G., González-Reyes, A. and Casanova, J. (2002) Cell surface proteins Nasrat and Polehole stabilize the Torso-like extracellular determinant in Drosophila oogenesis. Genes & Dev. 16, 913-918.
- Jiménez, G., Guichet, A., Ephrussi, A. and Casanova, J. (2000) Relief of gene repression by Torso RTK signaling: role of capicua in Drosophila terminal and dorsoventral patterning. Genes & Dev. 14, 224-231.
- Eberhard, D., Jiménez, G., Heavy, B. and Busslinger, M. (2000) Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. EMBO J. 19, 2292-2303.
- Jiménez, G., Verrijzer, C.P. and Ish-Horowicz, D. (1999) A conserved motif in Goosecoid mediates Groucho-dependent repression in Drosophilaembryos. Mol. Cell. Biol. 19, 2080-2087.
- Jiménez, G. and Ish-Horowicz, D. (1997) A chimeric Enhancer-of-split transcriptional activator drives neural development and achaete-scute expression. Mol. Cell. Biol. 17, 4355-4362.
- Jiménez, G., Paroush, Z. and Ish-Horowicz, D. (1997) Groucho acts as a corepressor for a subset of negative regulators, including Hairy and Engrailed. Genes & Dev. 11, 3072-3082.
- Jiménez, G., Pinchin, S.M. and Ish-Horowicz, D. (1996) In vivo interactions of the Drosophila Hairy and Runt transcriptional repressors with target promoters. EMBO J. 15, 7088-7098.
- Jiménez, G., Gale, K.B. and Enver, T. (1992) The mouse beta-globin Locus Control Region: hypersensitive sites 3 and 4. Nucleic Acids Res. 20, 5797-5803.
- Jiménez, G., Griffiths, S., Ford, A.M., Greaves, M.F. and Enver, T. (1992) Activation of the beta-globin Locus Control Region precedes commitment to the erythroid lineage. Proc. Natl. Acad. Sci. USA 89, 10618-10622.
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