GTPase-activating protein TBC1D5 coordinates with retromer to constrain synaptic growth by inhibiting BMP signaling

Xiu Zhou; Guangming Gan; Yichen Sun; Mengzhu Ou; Junhua Geng; Jing Wang; Xi Yang; Shu Huang; Da Jia; Wei Xie; Haihuai He

doi:10.1016/j.jgg.2022.11.009

Volume 50 Issue 3

Mar. 2023

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Article Navigation > Journal of Genetics and Genomics > 2023 > 50(3): 163-177

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GTPase-activating protein TBC1D5 coordinates with retromer to constrain synaptic growth by inhibiting BMP signaling

doi: 10.1016/j.jgg.2022.11.009

a. State Key Laboratory of Biotherapy, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China;
b. The Key Laboratory of Developmental Genes and Human Disease (MOE), School of Life Science and Technology, Southeast University, Nanjing, Jiangsu 210096, China;
c. The Key Laboratory of Developmental Genes and Human Disease (MOE), School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China;
d. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China

Funds:

We thank members of the He and Xie laboratory for suggestions and discussion during the course of this work. We further thank the Bloomington Stock Center, Vienna Drosophila Resource Center, and Tsinghua Fly Center for fly stocks. This work was supported by research grants from the National Natural Science Foundation of China (31671510 and 31871461 to H. H.

31771592 to W. X.).

Received Date: 2022-11-01
Accepted Date: 2022-11-22
Rev Recd Date: 2022-11-22
Publish Date: 2022-12-05

Abstract

Abstract

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.
- TBC1D5,
- NMJ,
- Synaptic growth,
- Retromer,
- BMP signaling

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References(73)

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