Axon stabilization: A role for glia in patterning adult innervation in Drosophila

描述(申请人提供)：我研究的长期目标是了解细胞-细胞交流的细胞和分子机制，该机制影响神经肌肉发育，包括功能性突触的形成。具体地说，我们将讨论影响果蝇发育中的成体神经重塑的神经-神经胶质相互作用的性质。我们以果蝇(成体)背纵(飞)肌的运动系统为模型。成年神经在变态期间发育，这一阶段的特点是包括神经系统在内的许多组织发生广泛的重塑。我们已经证明，运动神经元产生过多的二级分支，在这一阶段之后是一个修剪阶段，在此期间几乎70%的分支被消除。结果，建立了DLm神经支配的成体模式。这项建议侧重于一小部分运动神经元分支稳定下来以度过修剪阶段的方式，并测试胶质细胞在稳定过程中的作用。提出了三个主要目标：1)在神经发育的背景下研究胶质细胞的分化；2)通过控制胶质细胞的发育来测试其在稳定中的作用。3)研究细胞黏附分子Fas11在神经胶质细胞相互作用中的作用。有关果蝇神经肌肉发育的研究大多集中在幼虫期的发育可塑性，而成虫的发育仍有待于详细的研究。我们对运动轴突稳定性的研究将至少有四个目的：i)在三方突触的背景下检查神经肌肉系统的发育，其中不仅包括突触前和突触后的伙伴，还包括第三个重要的细胞，神经胶质细胞；ii)研究胶质细胞(在保护轴突分支中)的作用，这在果蝇中尚未报道；iii)在果蝇DLM神经支配的重塑过程中明显的发育可塑性要深刻得多，并且与脊椎动物神经系统发育过程中观察到的轴突修剪具有惊人的相似之处。此外，已知神经胶质细胞在脊椎动物神经肌肉发育过程中具有保护作用；因此，我们的系统可用作更好地了解脊椎动物事件的模型；iv)在更广泛的水平上，更好地了解神经胶质细胞的相互作用，这些相互作用已与人类疾病有关，如癫痫、精神分裂症、脑缺血、多发性硬化症以及神经退行性疾病。

DESCRIPTION (provided by applicant): The long-term goal of my research is to understand the cellular and molecular mechanisms of cell-cell communication that patterns neuromuscular development, including the formation of functional synapses. Specifically, we will address the nature of neuro-glial interactions that influence remodeling of the developing adult innervation in Drosophila. We use the motor system of the (adult) Dorsal Longitudinal (flight) Muscles of Drosophila as a model. The adult innervation develops during metamorphosis, a phase which is characterized by extensive remodeling of many tissues including the nervous system. We have shown that motor neurons elaborate excessive second order branches, and this period is followed by a phase of pruning during which almost 70% of the branches are eliminated. As a result, the adult pattern of DLM innervation is established. This proposal focuses on the manner in which a small subset of motor neuron branches is stabilized to survive the pruning phase, and tests the role of glia in the process of stabilization. Three main objectives are presented: 1) Examining the differentiation of glia in the context of the developing innervation; 2) Testing the role of glia in stabilization by manipulating their development. 3) Investigating the role of the cell-adhesion molecule, Fasll, in neuro-glial interactions. Most of the studies on neuromuscular development in Drosophila have focused on the developmental plasticity present in the larval stages, and development of the adult counterpart remains to be explored in the same detail. Our studies of motor axon stabilization will serve at least four purposes: i) examine development of the neuromuscular system in the context of a tripartite synapse, that includes not only the pre-and post synaptic partners but also a third important cell, the glia; ii) investigate a role for glia (in protection of axonal branches) that has not yet been reported in Drosophila; iii) The developmental plasticity evident during the remodeling of DLM innervation in Drosophila is much more profound and bears striking similarities to axonal pruning that is observed during vertebrate nervous system development. Additionally, glia are known to have protective roles during vertebrate neuromuscular development; thus our system can be used as a model for a better understanding of vertebrate events; iv) On a broader level, a better understanding neuro- glial interactions, which have been implicated in human conditions such as epilepsy, schizophrenia, cerebral ischemia, multiple sclerosis, as well as neurodegenerative diseases.