Growth Metabolism
and Physiology in Drosophila
Topics
Perturbation of homeostasis are critical for the progression of human diseases including metabolic syndrome, diabetes and cancers. Through the investigation of basal metabolism, we have shown that fatty acid synthesis is critical to protect against dietary sugar, in particular to prevent the formation of AGEs (Advanced Glycation End-products) (Figure 1) (https://doi.org/10.1371/journal.pgen.1004995), which are responsible for the deleterious effect of metabolic syndrome and diabetes. Further, activation of mTOR (mechanistic Target of Rapamycin) stimulates basal metabolism, potentially to sustain cell growth. mTOR is present in two distinct complexes, mTORC1 responds to nutrients, whereas mTORC2 acts downstream of insulin-like-peptide (ILp) signaling. In Drosophila, either signaling branch can be independently modulated and we have shown that cell-autonomous overgrowth induced by Ilp/mTORC2, but not mTORC1, is sensitive to basic metabolism (in press). Finally, we are currently studying the mechanisms of autophagy regulation by mTORC1 signaling.
Figure 1: Fatty acid synthesis and dietary sugar. The Drosophila fat body fulfils hepatic and adipose functions. Triacylglycerol synthesis is the main metabolic pathway limiting the formation of AGEs from the glycolytic triose-phosphate. Inhibition of fatty acid synthesis dramatically increases the synthesis of glycogen and AGEs and the latter become toxic at the organismal and cellular levels, in particular under a high sugar diet.
Sexual pheromones are essential to maintain species isolation. In insects, these chemical signals are produced in the oenocytes, which are cells specialized in lipid metabolism. In Drosophila larvae, we have shown that a specific very long chain fatty acid synthesized in the oenocytes is essential for waterproofing the tracheal system (https://doi.org/10.1371/journal.pgen.1002925). In collaboration with Claude Wicker-Thomas (EGCE, CNRS), we have shown that in the adult, the long chain fatty acids used as precursors of pheromone synthesis can have multiples origins, whereas the final steps of this synthesis takes place exclusively in the oenocytes (Figure 2) (doi: 10.1194/jlr.M060368). We are currently studying the role of oenocytes in female fertility.
Figure 2: Drosophila pheromones are hydro-carbons produced in the oenocytes from long chain fatty acids (LCFA). We have shown that these LCFA may originate from the oenocytes, but also depend on fat body metabolism and diet, whereas the final steps take place exclusively in the oenocytes.
Another part of the group is interested in how signaling pathways regulate and coordinate events during oogenesis. JAK/STAT pathway activation is required in a sequential manner during oogenesis for very diverse processes such as maintenance of germline stem cells, differentiation of several populations of somatic cells and the determination of the antero-posterior axis of the oocyte and future embryo. We have shown that the JAK/STAT pathway is strictly regulated during oogenesis, in particular through the control of the precise number of cells secreting a ligand for this signaling pathway by induction of apoptosis of supernumerary cells (doi: 10.1038/cddis.2017.166). Presently, we are exploiting the results of a genetic screen that identified several proteins interacting with the actin cytoskeleton as regulators of JAK/STAT signaling (thesis project, Figure 3).
Figure 3: In Drosophila ovarian follicles, robust JAK/STAT signaling requires proteins associated with the actin cytoskeleton. Images of one focal plane through the middle of Drosophila ovarian follicles ( fluorescent confocal microscopy). The wild-type oocyte (right) develops inside a follicle, surrounded by a mono-layered epithelium of somatic origin (Royal color code). At mid-oogenesis, exactly two specialized somatic cells called polar cells (red membrane marker and asterisks) are present at antero-posterior follicle extremities (anterior to the top). These cells are the only source for a ligand of the JAK/STAT signaling pathway in the ovary. The adjacent epithelial cells are highly activated for JAK/STAT signaling as evidenced by the expression of a STAT transcriptional reporter (Royal color code). Upon RNAi induced reduction in the follicle epithelium of one of several actin-associated proteins (left), activation of JAK/STAT signaling is significantly lower than in wild-type consistent with the fact that JAK/STAT-mediated apoptotic elimination of supernumerary polar cells has not occurred.
Tumor progression depends on intrinsic and extrinsic parameters. Our projects are connected to two Drosophila tumor models. On the one hand, we have shown that during development of the ovary, the transcription factors Bab1 and Bab2 are essential in somatic cell precursors for formation of the niches that recruit the initial germline stem cells (GSCs). In addition, this work shows that in the adult ovary (https://doi.org/10.1371/journal.pgen.1009128), overexpression of Bab proteins induces GSC tumors (Figure 4A). Identification of Bab protein targets in niche cells for initial GSC establishment and induction of GSC tumors will shed light on the mechanism by which these transcription factors regulate homeostasis of these stem cells. On the other hand, in collaboration with Fréderic Mery (EGCE, CNRS), we have investigated whether the social environment may affect tumor growth. In human, well-being is expected to favor patient recovery, although these issues cannot be directly addressed. We have used genetically induced intestinal tumors in Drosophila (Figure 4B) and shown that the social environment can modulate tumor growth (doi: 10.1038/s41467-018-05737-w). We are currently working to decipher the underlying physiological processes induced by the social interaction that control tumoral growth. Finally, we are also investigating the metabolic bases of these tumors.A
Figure 4 : Drosophila tumor models. (A) In the adult ovary (left), only two GSCs (arrows, cells marked by a round cytoplasmic structure in yellow called a spectrosome) are present in each niche. The overexpression of bab2 in all somatic cells of the ovary (right) leads to formation of tumors filled with germ cells (CG, red) with stem cell properties (spectrosomes in yellow). (B) Tumor in the anterior part of the midgut. A heat shock concurrently induces the loss of apc (adenomatous polyposis coli) and the expression of an oncogenic form of ras and of GFP in a few intestinal stem cells, which form solid tumors (green).