C 9: Regulation of C. elegans developmental timing by the F-box protein DRE-1/FBXO11
Prof. Dr. Adam Antebi
Max-Planck-Institut für Biologie des Alterns, Köln
email: aantebi@age.mpg.de
phone: +49-(0)221 478 89681
website
During metazoan development, cells acquire both positional and temporal identity. The C. elegans heterochronic loci encode temporal selectors that specify stage specific programmes during different larval stages, most visibly in epidermal stem cells but also in other tissues. Interestingly, their mammalian counterparts have been implicated in stem cell biology and differentiation. We have identified a new heterochronic gene product, DRE-1, which functions in larval to adult transitions in epidermis and gonad. DRE-1 is an ortholog of a highly conserved mammalian F-box protein, FBXO11, and works as part of a SCF E3-ubiquitin ligase complex, together with CUL-1, SKP-1 and RBX-1/2 components, implicating post-translational ubiquitin-mediated modification and proteolysis in developmental timing. However, DRE-1 substrate(s) remain unknown. The overall goal of this proposal is to dissect how the DRE-1/E3 ligase complex regulates developmental timing and to identify DRE-1 substrates. We will identify DRE-1 substrates by immunoprecipitation of complexes and analysis by mass spectrometry, yeast two-hybrid analysis, as well as by performing dre-1 suppressor screens. Identified substrates will be functionally analysed for the role of ubiquitylation in modulating their activity. To further understand function and help identify relevant substrates for developmental timing, we will place dre-1 into subpathways of the heterochronic circuit, determine in which tissues it acts, and perform structure function analysis of the protein. Such studies should yield fundamental insights into post-translational mechanisms regulating metazoan developmental timing, stem cell biology, and their dysregulation in cancer and aging.
Running time: 07/2011 – 06/2015
Recent publications:
Horn, M., Geisen, C., Becker, B., Nakamura, S., Klein, C., Cermak, L., Pagano, M., and Antebi, A. (2014). DRE-1/FBXO11 dependent degradation of BLMP-1/BLIMP-1 governs C. elegans developmental timing and maturation. Developmental Cell 28, 697-710. Pubmed.
Rossi,. M., Duan, S., Jeong, Y.T., Horn, M., Saraf, A., Florens, L., Washburn, M.P., Antebi, A., and M. Pagano (2013). Regulation of the CRL4Cdt2 ubiquitin ligase and cell cycle exit by the SCFFbxo11 ubiquitin ligase. Molecular Cell 49, 1159-66. PubMed
Bethke, A., Fielenbach, N., Wang, Z., Mangelsdorf, D.J., and Antebi, A. (2009). Nuclear hormone receptor regulation of microRNAs controls developmental progression. Science 324, 95-98.
Magner, D.B. and Antebi, A. (2008). Caenorhabditis elegans nuclear receptors: insights into life traits. Trends Endocrinol. Metab. 19, 153-160. (review)
Fielenbach, N. and Antebi, A. (2008). C. elegans dauer formation and the molecular basis of plasticity. Genes Dev. 22, 2149-2165. (review)
Fielenbach, N., Guardavaccaro, D., Neubert, K., Chan, T., Li, D., Feng, Q., Hutter, H., Pagano, M., and Antebi, A. (2007). DRE-1: an evolutionarily conserved F box protein that regulates C. elegans developmental age. Dev. Cell 12, 443-455.
Motola, D., Cummins, C.L., Rottiers, V., Sharma, K., Sunino, K., Xu, E., Auchus, R., Antebi, A., and Mangelsdorf, D. (2006). Identification of hormonal ligands for DAF-12 that govern dauer formation and reproduction in C. elegans. Cell 124, 1209-23.
Antebi, A., Yeh, W.H., Tait, D., Hedgecock, E.M., and Riddle, D. (2000). daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans. Genes Dev. 14, 1512-1527.
Antebi, A., Culotti, J.G., and Hedgecock, E.M. (1998). daf-12 regulates developmental age and the dauer alternative in C. elegans. Development 125, 1191-1205.