Abstract: Cağhan KIZIL

Understanding the molecular programs that underlie the induced plasticity and regeneration in adult vertebrate brains

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Ca?han K?z?l

German Center for Neurodegenerative Diseases (DZNE) Dresden, Helmholtz Association
DFG-Research Center for Regenerative Therapies , Dresden
Cluster of Excellence at the TU Dresden (CRTD), Dresden, Germany

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The vertebrate brains display a large variety of neural plasticity, which includes the dynamic modulation of the synapses and activation of neural stem cells (NSC). However, the plastic nature of the adult neural stem cells in case of damage is manifested differently among vertebrates. For instance, the adult zebrafish brain constitutively produces new neurons and regenerate after injuries upon injury-dependent activity of NSCs. This is in stark contrast to mammalian brains, which poorly regenerate, despite prevalent adult neurogenesis in two neurogenic niches of the forebrain. We hypothesized that the disparity between the regenerative capacities of the central nervous system (CNS) of these animals might be stemmed from the prevalence of specific molecular programs that are turned on only after the damage. These mechanisms are likely to be responsible for the induced plasticity of NSCs and a detailed understanding of those programs could be harnessed for regenerative therapies in humans. We identified a novel molecular pathway including the activity of the transcription factor gata3, which is induced upon injury and is required for the specific regenerative success in zebrafish. We also found that inflammatory cues regulate the regenerative onset such as acute inflammation through LTC4/Cystlr1 signalling is a cue that triggers specific regeneration programs in zebrafish neural progenitor cells and the chemokine signalling through cxcr5 potentiates the regenerative neurogenesis at the level of neuronal differentiation. Additionally, our results suggest that forced-expression of regeneration-factors in mammalian glial cells – which are in various culture and in vivo conditions non-neurogenic - impose a regenerative neurogenic capacity to those neuronal precursor cells, suggesting that what we learn from zebrafish may help design regenerative therapies in mammals using their endogenous progenitors. These results collectively provide an important fulcrum to the hypothesis that special regenerative programs that enable tissue replenishment might exist in regenerating organisms and understanding such programs would endow us to use those mechanisms in efforts for clinical settings for neurodegenerative disorders or acute injuries in human CNS. In our lab we are expanding our investigation of plasticity programs to chronic neurodegeneration and activity-dependent neurogenesis in adult zebrafish brain by generating conditional genetic models and manual manipulation methods.