Research project P7/20 (Research action P7)
The function of the nervous system requires formation, plasticity, maintenance and repair of its wiring diagram. To connect appropriately, neurons need to be specified and to migrate to their correct positions before they grow axons which are guided to target territories by intrinsic programs, guidepost cells and a variety of attractive and repulsive cues. In parallel, neurons ramify receptive dendritic fields by following strict “tiling” rules. Synapses are then formed and refined progressively, resulting in functional networks. Networks are plastic and dynamic, responsive to environmental challenges that occur during normal life or result from disease and trauma. All these events are controlled by a variety of activity-dependent and independent mechanisms. Understanding neural wiring is critical to optimally harness the potential of neurons or stem cells, in order to palliate neurological deficits. As far as we know, no concerted action at the Belgian level has previously been focused on this important theme.
“Wiring the brain” (WIBRAIN) is thus a new initiative aiming to understand critical regulators of neural wiring, from Drosophila to human, using a panel of molecular, genetic, neurophysiological, morphological and behavioral approaches. It focuses operationally on the five workpackages outlined below, carefully selected to address the key issues in the field, to fit the competitive edge of the partners, to emphasize multidisciplinarity and translational potential, and to take advantage of synergies between the partners.
WIBRAIN stems from a strong commitment by all partners to pool their professional expertise and make significant contributions to the wide field of brain wiring. More than thirty publications in top journals (IF>10), including Cell, Nature and Science, over the last six years provide evidence that the partners in this proposal are leaders in their field, with a solid international reputation and a demonstrated capacity to innovate. With the exception of the coordinator, partners ULB and KUL are in their forties, at the peak of their productivity, and ULG and UA qualify as emerging teams. Foreign partners were chosen based on their expertise. Dr Berninger (JGU) studies mechanisms of adult neural stem cell lineage progression and cell fate specification using time-lapse imaging, and the conversion of somatic cells such as astroglia or pericyte-derived cells into functional neurons. He also has expertise in electrophysiology and retroviral gene transfer. Dr Reiff (UFR) is an expert on functional and physiological analysis of neural circuits in Drosophila. He has developed one of the best genetically encoded Ca-sensors and combines genetics and 2-photon imaging to dissect the interrelation of neuronal circuit anatomy and its functionality as assessed by electrophysiological recordings, combined with behavioral analysis.
The project seeks to address key questions about brain wiring and is organized into five work packages (WP), with selected prioritized tasks (T).
WP1. Neuronal specification and migration
T1.1 Neural stem cell specification. Control of neural stem cell specification by transcription factors and Notch signaling.
T1.2. Neuro-epithelial polarity. Polarization of the neuroepithelium, control of interkinetic movement. Role of cytoskeletal regulators, planar cell polarity (PCP) genes, centrosomal and ciliary proteins.
T1.3 Neuronal migration. Microtubule dynamics, oxygen sensors, metabolic genes, PCP and formins.
WP2. Axonal growth and targeting
T2.1. Axon guidance. Control of outgrowth and targeting by kinases identified by novel screens in flies, Notch signaling, PCP genes and the cytoskeletal regulators.
T2.2. Axon branching and pruning. Regulation of axon branching and pruning by activity, intrinsic programs and target-derived signals. Computational modeling of axon/target and axon/axon interactions.
WP3. Formation of dendritic fields
T3.1. Maturation, self avoidance and tiling. Reciprocal inhibition /self-avoidance in dendritic field maturation and effects on neural network activity. Role of DSCAM and DSCAM-related receptors.
T3.2. Role of oxygen sensors and metabolism.
T3.3. Cortical area formation. Role of Bcl6, Eph-Ephrins, and Lrrn1-3 (Leucine-rich repeat neuronal proteins 1-3).
WP4. Synapse formation and activity
T4.1. Identification of novel genes. Spatial and functional specificity in synapse address selection. Role of surface receptors identified in genetic screens in flies.
T4.2. Genesis of patterned electrical activity. Emergence of patterned activity from microcircuitry. Effect of mutations or downregulation of genes of interest mentioned in WP1-WP4.1.
WP5. Brain repair
T5.1. Strategies involving generation of new neural cells. Directed differentiation of mouse and human pluripotent stem cells, reprogramming into neurons and validation in animal models for brain repair.
T5.2. Strategies involving axon regeneration from existing neurons. Axonal regeneration and rewiring in vivo following lesions.
