Zhou Xiu, Gan Guangming, Sun Yichen, Ou Mengzhu, Geng Junhua, Wang Jing, Yang Xi, Huang Shu, Jia Da, Xie Wei, He Haihuai
State Key Laboratory of Biotherapy, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
The Key Laboratory of Developmental Genes and Human Disease (MOE), School of Life Science and Technology, Southeast University, Nanjing, Jiangsu 210096, China; The Key Laboratory of Developmental Genes and Human Disease (MOE), School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
J Genet Genomics. 2023 Mar;50(3):163-177. doi: 10.1016/j.jgg.2022.11.009. Epub 2022 Dec 5.
Formation and plasticity of neural circuits rely on precise regulation of synaptic growth. At Drosophila neuromuscular junction (NMJ), Bone Morphogenetic Protein (BMP) signaling is critical for many aspects of synapse formation and function. The evolutionarily conserved retromer complex and its associated GTPase-activating protein TBC1D5 are critical regulators of membrane trafficking and cellular signaling. However, their functions in regulating the formation of NMJ are less understood. Here, we report that TBC1D5 is required for inhibition of synaptic growth, and loss of TBC1D5 leads to abnormal presynaptic terminal development, including excessive satellite boutons and branch formation. Ultrastructure analysis reveals that the size of synaptic vesicles and the density of subsynaptic reticulum are increased in TBC1D5 mutant boutons. Disruption of interactions of TBC1D5 with Rab7 and retromer phenocopies the loss of TBC1D5. Unexpectedly, we find that TBC1D5 is functionally linked to Rab6, in addition to Rab7, to regulate synaptic growth. Mechanistically, we show that loss of TBC1D5 leads to upregulated BMP signaling by increasing the protein level of BMP type II receptor Wishful Thinking (Wit) at NMJ. Overall, our data establish that TBC1D5 in coordination with retromer constrains synaptic growth by regulating Rab7 activity, which negatively regulates BMP signaling through inhibiting Wit level.
神经回路的形成和可塑性依赖于突触生长的精确调控。在果蝇神经肌肉接头（NMJ）处，骨形态发生蛋白（BMP）信号传导对于突触形成和功能的许多方面都至关重要。进化上保守的逆转录复合物及其相关的GTP酶激活蛋白TBC1D5是膜运输和细胞信号传导的关键调节因子。然而，它们在调节NMJ形成中的功能尚不清楚。在这里，我们报告TBC1D5是抑制突触生长所必需的，TBC1D5的缺失会导致突触前末端发育异常，包括过多的卫星小体和分支形成。超微结构分析显示，在TBC1D5突变小体中，突触小泡的大小和突触下网状结构的密度增加。TBC1D5与Rab7和逆转录复合物相互作用的破坏模拟了TBC1D5的缺失。出乎意料的是，我们发现TBC1D5除了与Rab7功能相关外，还与Rab6功能相关，以调节突触生长。从机制上讲，我们表明TBC1D5的缺失通过增加NMJ处BMP II型受体如意算盘（Wit）的蛋白质水平导致BMP信号传导上调。总体而言，我们的数据表明，TBC1D5与逆转录复合物协同作用，通过调节Rab7活性来限制突触生长，Rab7活性通过抑制Wit水平对BMP信号传导起负调节作用。
