Determination of cellular identity is crucial in a variety of developmental frameworks. Fate specification typically involves an initial identity/pathway choice, which can be either deterministic or stochastic. Once selected this identity is reinforced and remembered using mechanisms that are often distinct from those deployed in the initial choice. Lastly, the chosen pathway must be faithfully executed so that cells differentiate appropriately. Over the years, we?ve investigated the process of cell fate specification in several distinct developmental contexts using the genetically tractable fruit fly, Drosophila melanogaster as our model system. Depending on the developmental pathway and the ?step? in the specification process (e.g., pathway maintenance) the precise molecular mechanisms needed for proper specification can be at many different levels (cell-cell signaling, transcription, splicing, chromosome structure). In the first part of this proposal we examine the specification of primordial germ cells (PGCs) in the early embryo. In mammals PGC specification depends upon inductive BMP and Wnt signals. In contrast, in multicellular animals other than mammals, PGC specification has long been thought to be a cell-autonomous process that depends upon maternally deposited factors. However, we have recently discovered that BMP signals from somatic cells play an important role in PGC specification in the fly. This discovery suggests that the process of PGC specification across the animal kingdom may be much more similar than previously believed. Our proposed experiments are directed towards understanding the functional coordination between the cell autonomous factors and the BMP pathway during acquisition and maintenance of PGC identity. The second part of the proposal is focused on chromosome architectural elements (boundary elements, Polycomb Response Elements and Chromatin Entry Sites). The proposed experiments will examine how these elements function to determine the topological organization of eukaryotic chromosomes. We will also explore how the activities of these elements impact pathway initiation, memory and execution in several distinct developmental pathways.
This MIRA application focuses on two areas of biology that are important in understanding human development and the etiology of diseases, germline development and chromosome structure. A detailed understanding of factors critical to germline development will be important in treating diseases that impact fertility. It is equally important to elucidate the organization of chromosomes inside the nucleus as it impacts gene regulation and is thus crucial in tackling many disease conditions.
| Kyrchanova, Olga; Kurbidaeva, Amina; Sabirov, Marat et al. (2018) The bithorax complex iab-7 Polycomb response element has a novel role in the functioning of the Fab-7 chromatin boundary. PLoS Genet 14:e1007442 |
| Fedotova, Anna; Aoki, Tsutomu; Rossier, Mikaël et al. (2018) The BEN Domain Protein Insensitive Binds to the Fab-7 Chromatin Boundary To Establish Proper Segmental Identity in Drosophila. Genetics 210:573-585 |
