Neural stem cell and niche interplays during Drosophila neurogenesis – NeuraSteNic

The brain is plastic throughout life. It is able to integrate both intrinsinc, developmental and homeostatic cues, as well as extrinsic, environmental changes. The integration and mediation by the brain of this combinatorial input can result in a wide spectrum of positive or negative outcomes at the neurological, cognitive or mental levels. The existence of such plasticity and the potentiality to direct it opens up tremendous promises for health maintenance and treatments of brain diseases. Understanding its cellular mechanisms is a prerequisite to identifying the appropriate parameters to manipulate for health benefits.
Neural stem cells are key players supporting brain plasticity. They are in charge of neurogenesis from development to adulthood. As such they can produce new neurons or glial cells, leading the brain to either acquire new functions or to replace lost functions. Neural stem cells are found in a specific, tailored cellular microenvironment, or niche. The niche must adjust its functions to mediate the impact of local and external signals on neural stem cells, which could in turn feedback to amend the niche to their needs. How and to what extent remains poorly understood. We want to understand how these two populations shape and modulate each other in order to sustain neurogenesis during physiological growth, as well as how these interactions change under pathological conditions.
Progress on these outstanding issues has been hampered by the complexity of the vertebrate niche as well as by the difficulty of accessing a whole living brain. We propose to decipher the core mechanisms underlying neural stem cell and niche interactions using a powerful and versatile genetic model, Drosophila melanogaster. Albeit a simpler model allowing a complete in vivo approach, the Drosophila neural stem cell niche encompasses key actors of the vertebrate niche, such as glial cells and blood-brain barrier. Drosophila neural stem cells self-renew to produce new progeny, and are able to reactivate from a quiescent, dormant state to proliferate.
We have previously shown that in post-embryonic, larval stages, a specific glial population is able to remodel its structure in response to neural stem cell reactivation. This adaptation is in turn critical for sustaining neurogenesis, and ultimately generating the adult nervous system. This is a paradigm of how neural stem cells and glial niches shape and modulate each other in physiological conditions.
We now want to decipher the nature of this communication as well as how and why glial cells adapt their structure to neural stem cells’ needs during normal neurogenesis. To this purpose, we will first characterise the exact architecture of the glial niche around the neural stem cells. In addition we will use a transcriptional approach, followed by a carefully targeted genetic screen, to identify molecular players.
In parallel, we also want to investigate to which extent the interplays beween glia and stem cells remodel under an external, aggressive stress, bacterial infection. This is a challenging project, and there is so far no model of brain infection in Drosophila. Promising preliminary results have identified a human pathogen able to pass the Drosophila blood-brain barrier and infect its brain both ex vivo and in vivo. Moreover, this infection leads to altered neural stem cell and glia morphologies. We now want to investigate the events triggered in the neural stem cell niche upon infection, from morphological and functional changes to inflammation markers.
Our project investigates the dynamics of interactions between neural stem cells and their niche in Drosophila both under physiological growth and infection. These complementary approaches will provide us with a better knowledge of the core cellular mechanisms supporting brain plasticity in health and diseases.