Department of Molecular Cell Biology, Weizmann Institute of Sciences, Rehovot 76100, Israel.
Department of Molecular Cell Biology, Weizmann Institute of Sciences, Rehovot 76100, Israel.
Dev Cell. 2014 Nov 24;31(4):461-73. doi: 10.1016/j.devcel.2014.10.013.
Developmental axon pruning is essential for wiring the mature nervous system, but its regulation remains poorly understood. Here we show that the endosomal-lysosomal pathway regulates developmental pruning of Drosophila mushroom body γ neurons. We demonstrate that the UV radiation resistance-associated gene (UVRAG) functions together with all core components of the phosphatidylinositol 3-kinase class III (PI3K-cIII) complex to promote pruning via the endocytic pathway. By studying several PI(3)P binding proteins, we found that Hrs, a subunit of the ESCRT-0 complex, required for multivesicular body (MVB) maturation, is essential for normal pruning progression. Thus, we hypothesized the existence of an inhibitory signal that needs to be downregulated. Finally, our data suggest that the Hedgehog receptor, Patched, is the source of this inhibitory signal likely functioning in a Smo-independent manner. Taken together, our in vivo study demonstrates that the PI3K-cIII complex is essential for downregulating Patched via the endosomal-lysosomal pathway to execute axon pruning.
发育中的轴突修剪对于成熟神经系统的布线至关重要，但对其调控机制仍知之甚少。本文中，我们发现内体-溶酶体途径调控果蝇蘑菇体γ神经元的发育性修剪。研究表明，紫外线辐射抗性相关基因（UVRAG）与磷脂酰肌醇 3-激酶 III 类（PI3K-cIII）复合物的所有核心成分共同作用，通过内吞途径促进修剪。通过研究几种 PI(3)P 结合蛋白，我们发现 Hrs，ESCRT-0 复合物的一个亚基，对于多泡体（MVB）成熟是必需的，对于正常的修剪过程是必需的。因此，我们假设存在需要下调的抑制信号。最后，我们的数据表明，Hedgehog 受体 Patched 是这种抑制信号的来源，可能以 Smo 非依赖的方式发挥作用。综上所述，本体内在研究表明，PI3K-cIII 复合物通过内体-溶酶体途径下调 Patched 对于执行轴突修剪是必需的。
