Our lab is interested in the mechanisms that underlie the development and differentiation of neuronal lineages. We use genetic and molecular approaches to unravel the regulatory interactions and signaling pathways which determine neural precursor cells and lead to the differentiation of functional neuronal elements. Our main tool is the fruit fly Drosophila melanogaster. Our main goal is to unravel the genetic interactions which control the behavior of neurons from their specification to the establishment of neuronal connectivity and neuronal circuits. We also have an interest in understanding how neurons respond to perturbations in their connectivity patterns, such as those resulting from axonal injury, and how they act to re-establish injured circuits.

to achieve these goals we have established three major lines of research

• Transcriptional gene regulatory networks (GRNs) in fate specification and Cancer

Postdocs: Xiao-Jiang Quan, Ariane Ramaekers

Ph.D. Students: Duygu Esen, Liqun Yuan

Proneural genes, particularly transcription factors of the basic-Helix-Loop-Helix super family, are the key determinants of neuronal fate in the nervous systems of all animals. We know these genes sit on top of a hierarchy of events that result in the induction of differentiation in nascent neural precursors cells and we know they must do so by regulating gene expression (reviewed in Quan and Hassan 2005). What we don't know is how they do it, how many genes they regulate and what is the structure of the gene regulatory network that emanates from their activity. To address this question we use the Atonal bHLH proneural gene, which specifies neural fate in many PNS tissues, including the fly retina. Our recent data suggest a model in which the coordinate and combinatorial regulation of the intracellular signaling state of cells by Atonal is the initiating event in (Aerts et al., 2010). The discovery of Atonal as a tumor suppressor gene (Bossuyt et al., 2009) means that it's regulatory network may be implicated intimately with cancer initiation and progression.

• Neuronal circuit development in the fly visual system

Postdocs: Ariane Ramaekers

Ph.D. students: Marion Langen, Marlen Schlieder, Laura Nicolaï

How do neurons make their connectivity decisions? Are they programmed to do so by some innate, cell autonomous, genetic program? In other words, is the development of the brain hard wired? Or are neurons born with a wide range of choices which are progressively narrowed down through synaptic activity-dependent interactions between them? There is little disagreement among neuroscientists that synaptic activity dependent mechanisms are important in the brain maintenance and in our capacity to acquire new knowledge and store memories. In contrast there is a sharp difference between scientists on how early these mechanisms start to act and what role they play, if any, in the development of the initial architecture of the brain. The reason this is such an important issue is that the hard wiring model, if true, implies that our capacity to acquire knowledge is largely pre-figured by the our genes and would likely shift the attention of cognitive neuroscience significantly towards genetic mechanisms of behaviour.

The issue we try to address in the lab is the extent to which it is possible to construct an exquisitely patterned diagram of neuronal connections using genetically determined versus activity-dependent mechanisms. To this end we use a set of visual system neurons called the DCN (Hassan et al., 2000). These neurons have a very stereotypical arrangement of axons and axonal branches that innervate two different areas, called the lobula and the medulla, in the fly visual system. The evidence we have so far says that the choice of the precise number of axons in the lobula versus the medulla is genetically determined and activity-independent (Srahna et al., 2006). What we are now trying to determine is whether the precise arrangement of these axons, their branches and their synaptic boutons is also genetically determined and if so, how: what are genes, how do they interact and how do the cells communicate their decisions to their neighbours. Conversely we are asking if genes involved in activity play a role in shaping brain development. To do this we combine novel markers of neuronal compartments (Nicolaï et al., 2010), classical forward and reverse genetic approaches with computational modeling, population level variation analysis and, of course, high resolution imaging.

 

 

• Axonal pathology, injury and regeneration in the fly CNS

Postdocs: Marta Koch

Ph.D. students: Alessia Soldano, Zeynep Okray, Maya Nicolas

This is our newest endeavour! Can injured axons regenerate and if so, what are the necessary manipulation that will cause them to do so? To tackle this issue we have been developing two novel approaches. The first is to create a novel and very precise CNS axon injury paradigm, based on long-term whole adult brain explant culture, and ask if injured fly CNS axons can regenerate. They cannot! This gives us the opportunity to search for genes which, when activated, might help severed axons regrow. Our evidence so far indicates that the brain responds to injury by up-regulating several signaling molecules (Leyssen et al., 2005). We also have evidence that these molecules, if sufficiently upregulated, can induced injured adult CNS axons to regenerate new axonal sprouts and in some cases target them towards and beyond the injury site (Ayaz et al., 2008). A second approach is to ask what the normal function of CNS disease causing genes is. Obviously no gene evolves just to cause disease, and our work shows that such genes have important functions during axonal outgrowth suggesting that it is the alteration of these functions that results in the pathology (Reeve et al., 2005 and 2008).