EGFR-dependent suppression of synaptic autophagy is required for neuronal circuit development
EGFR-dependent suppression of synaptic autophagy is required for neuronal circuit development
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DOI：
10.1016/j.cub.2022.12.039
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发表时间：
2023-02-06
期刊：
影响因子：
9.2
通讯作者：
Hassan, Bassem A.
中科院分区：
文献类型：
--
作者：
Dutta, Suchetana B.;Linneweber, Gerit Arne;Hassan, Bassem A.
神经元连接的发展需要联会形成部位的动态轴突分支的稳定。解释轴突分支如何与突触发生相耦合的模型假设，分子调节分子以时空受限的方式发挥作用，以确保向未来的突触伙伴分支，同时也稳定这些伙伴之间新出现的突触联系。我们以果蝇大脑的神经元回路发育为模型系统来研究这个问题。我们报道了在果蝇发育的视觉系统中，突触前轴突在两个不同的时间间隔内需要表皮生长因子受体(EGFR)的活性来调节回路的连接。早期需要EGFR来调节初级轴突分支。在较晚的阶段，EGFR的活性是独立需要的，以防止突触活动区蛋白Bruchilot(BRP)的降解。EGFR失活导致突触前分支局部自噬增加，活动区蛋白移位到自噬小泡中。在这个较晚的连接间隔期间，突触材料的保护确保了终末分支、电路连接和适当的视觉行为的稳定。EGFR失活的表型可以通过增加BRP水平或下调自噬来挽救。综上所述，我们确定了轴突分支和突触稳定耦合所需的时间受限的分子机制，该机制有助于神经元连接特异性的出现。
The development of neuronal connectivity requires stabilization of dynamic axonal branches at sites of syn-apse formation. Models that explain how axonal branching is coupled to synaptogenesis postulate molecular regulators acting in a spatiotemporally restricted fashion to ensure branching toward future synaptic partners while also stabilizing the emerging synaptic contacts between such partners. We investigated this question using neuronal circuit development in the Drosophila brain as a model system. We report that epidermal growth factor receptor (EGFR) activity is required in presynaptic axonal branches during two distinct tempo-ral intervals to regulate circuit wiring in the developing Drosophila visual system. EGFR is required early to regulate primary axonal branching. EGFR activity is then independently required at a later stage to prevent degradation of the synaptic active zone protein Bruchpilot (Brp). Inactivation of EGFR results in a local in-crease of autophagy in presynaptic branches and the translocation of active zone proteins into autophagic vesicles. The protection of synaptic material during this later interval of wiring ensures the stabilization of ter-minal branches, circuit connectivity, and appropriate visual behavior. Phenotypes of EGFR inactivation can be rescued by increasing Brp levels or downregulating autophagy. In summary, we identify a temporally restricted molecular mechanism required for coupling axonal branching and synaptic stabilization that con-tributes to the emergence of neuronal wiring specificity.