Roles of mitochondria and inhibitor of apoptosis proteins in the spatial and temporal regulation of caspase activation during axonal arborisation and degeneration

我们研究的总体目标是了解轴突分支和突触形成的细胞和分子机制，这是建立神经元连接的关键步骤。我们以斑马鱼视觉系统为模型，利用视网膜神经节细胞轴突乔木研究乔木化和突触形成的细胞和分子机制。我们可以进行体内成像来跟踪它们的动态，并操纵潜在基因发挥作用的功能。我们发现线粒体优先定位于稳定的突触前位点和分支，而不是新的/年轻的高度动态的分支尖端和突触前位点。这些数据表明，线粒体可能在稳定的突触中发挥作用，这些突触更有可能在神经元回路中具有电活性，而在这些回路中，需要大量的ATP来维持神经活动。我们还监测了在神经退行性变发病时视网膜轴突的半胱天冬酶活性的快速转换。空间受限的半胱天酶激活向更广泛的范围丧失，这可能导致观察到的神经变性。其机制目前尚不清楚-允许快速和更多空间限制的半胱天冬酶激活。

The overall aim of our research is to understand the cellular and molecular mechanisms of axonal branching and synapse formation, key steps in the establishment of neuronal connectivity. We use the zebrafish visual system as a model for studying the cellular and molecular mechanisms of arborisation and synapse formation using the retinal ganglion cell axon arbors. We can perform in vivo imaging to follow their dynamics and manipulated the the function of potential genes playing roles. We have found that mitochondria are preferentially localised to stable presynaptic sites and branches rather than in the new / young highly dynamic branch tips and presynaptic sites. These data suggest that mitochondria may play roles at stable synapses that are more likely to be electrically active in neuronal circuits where higher amounts of ATP are necessary to maintain neural activity. We have also monitored a rapid switch in caspase activity in retinal axon arbors at the onset of neurodegeneration. There is a loss of spatially restricted caspase activation to a more widespread which may contribute to the neural degeneration observed. The mechanisms of which are currently unknown - to allow rapid and more spatially restricted caspase activation.