Notch and Prospero Repress Proliferation following Cyclin E Overexpression in the Drosophila Bristle Lineage

Understanding the mechanisms that coordinate cell proliferation, cell cycle arrest, and cell differentiation is essential to address the problem of how “normal” versus pathological developmental processes take place. In the bristle lineage of the adult fly, we have tested the capacity of post-mitotic cells to re-enter the cell cycle in response to the overexpression of cyclin E. We show that only terminal cells in which the identity is independent of Notch pathway undergo extra divisions after CycE overexpression. Our analysis shows that the responsiveness of cells to forced proliferation depends on both Prospero, a fate determinant, and on the level of Notch pathway activity. Our results demonstrate that the terminal quiescent state and differentiation are regulated by two parallel mechanisms acting simultaneously on fate acquisition and cell cycle progression

S-Phase Favours Notch Cell Responsiveness in the Drosophila Bristle Lineage

We have studied cell sensitivity to Notch pathway signalling throughout the cell cycle. As model system, we used the Drosophila bristle lineage where at each division N plays a crucial role in fate determination. Using in vivo imaging, we followed this lineage and activated the N-pathway at different moments of the secondary precursor cell cycle. We show that cells are more susceptible to respond to N-signalling during the S-phase. Thus, the period of heightened sensitivity coincided with the period of the S-phase. More importantly, modifications of S-phase temporality induced corresponding changes in the period of the cell's reactivity to N-activation. Moreover, S-phase abolition was correlated with a decrease in the expression of tramtrack, a downstream N-target gene. Finally, N cell responsiveness was modified after changes in chromatin packaging. We suggest that high-order chromatin structures associated with the S-phase create favourable conditions that increase the efficiency of the transcriptional machinery with respect to N-target genes

Cycle et détermination cellulaire (multiples rôles de la cycline A dans le lignage des soies mécano-sensorielles chez la drosophile)

La coordination entre le cycle et la détermination cellulaire est un processus clé du développement. Au cours de ma thèse, j ai analysé le rôle de la Cycline A, une cycline mitotique, lors de deux évènements qui illustrent cette coordination : les endocycles et la division asymétrique. L endocycle est un variant du cycle cellulaire canonique composé uniquement de phases de réplication et de phases Gap aboutissant à la formation de cellules polyploïdes. Ce variant est associé à des cellules en différentiation terminale et permet d augmenter leurs capacités métaboliques. La division asymétrique quant-à elle, induit la formation de cellules d identités différentes via la ségrégation asymétrique de facteurs de détermination dans les deux cellules filles. J ai utilisé comme système modèle le lignage des soies mécano-sensorielles. J ai ainsi pu mettre en évidence d une part un rôle de CycA dans le contrôle de la dynamique des endocycles. Mes résultats suggèrent notamment que cette régulation passe par un contrôle de la localisation de la protéine ORC2, un membre des complexes de pré-réplication. D autre part, j ai également observé une localisation asymétrique de CycA au cours de la division de la cellule pI, le précurseur du lignage. De plus, il est intéressant de noter que cycA et le modulateur de la voie Notch, deltex interagissent génétiquement, suggérant une implication de CycA dans l activation différentielle de la voie Notch dans les deux cellules filles de pI. L ensemble de mes résultats montre ainsi que CycA assure de multiples rôles au cours du développement des organes mécano-sensoriels permettant ainsi la coordination entre cycle et détermination cellulaire.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Cell cycle and cell-fate determination in Drosophila neural cell lineages

‘Normal' development requires a finely tuned equilibrium between cell differentiation and cell proliferation. Important issues in development include whether the cell cycle controls the cell-fate determination and whether cell identity in turn regulates cell-cycle progression. Although, these issues are of general biological relevance, stereotyped Drosophila neural lineages are particularly suited to address these questions and have provided insights into the links between cell-cycle progression and cell-fate specification

A neural progenitor mitotic wave is required for asynchronous axon outgrowth and morphology

Spatiotemporal mechanisms generating neural diversity are fundamental for understanding neural processes. Here, we investigated how neural connection diversity arises from neurons coming from identical progenitors. In the dorsal thorax of Drosophila, rows of mechanosensory organs originate from the division of sensory organ progenitor (SOPs). We show that in each row of the notum, a central SOP divides first, then neighboring SOPs divide, and so on. This centrifugal wave of mitoses depends on cell-cell inhibitory interactions mediated by SOP cytoplasmic protrusions and Scabrous, a secreted protein interacting with the Delta/Notch complex. When scabrous was downregulated, the mitotic wave was abolished, axonal growth was more synchronous, axonal terminals had a complex branching pattern and fly behavior was impaired. We propose that the temporal order of progenitor divisions influences the birth order of sensory neurons which is critical for correct axon wiring and appropriate grooming behavior, supporting the idea that developmental timing controls neural connectivity

Shaping of Drosophila neural cell lineages through coordination of cell proliferation and cell fate by the BTB-ZF transcription factor Tramtrack-69

International audienceCell diversity in multicellular organisms relies on coordination between cell proliferation and the acquisition of cell identity. The equilibrium between these two processes is essential to assure the correct number of determined cells at a given time at a given place. Using genetic approaches and correlative microscopy, we show that Tramtrack-69 (Ttk69, a Broad-complex, Tramtrack and Bric-à-brac - Zinc Finger (BTB-ZF) transcription factor ortholog of the human promyelocytic leukemia zinc finger factor) plays an essential role in controlling this balance. In the Drosophila bristle cell lineage, which produces the external sensory organs composed by a neuron and accessory cells, we show that ttk69 loss-of-function leads to supplementary neural-type cells at the expense of accessory cells. Our data indicate that Ttk69 (1) promotes cell cycle exit of newborn terminal cells by downregulating CycE, the principal cyclin involved in S-phase entry, and (2) regulates cell-fate acquisition and terminal differentiation, by downregulating the expression of hamlet and upregulating that of Suppressor of Hairless, two transcription factors involved in neural-fate acquisition and accessory cell differentiation, respectively. Thus, Ttk69 plays a central role in shaping neural cell lineages by integrating molecular mechanisms that regulate progenitor cell cycle exit and cell-fate commitment