Neuronal GAP-Porf-2 transduces EphB1 signaling to brake axon growth
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Axonal outgrowth and guidance require numerous extracellular cues and intracellular mediators that transduce signals in the growth cone to regulate cytoskeletal dynamics. However, the way in which cytoskeletal effectors respond to these signals remains elusive. Here, we demonstrate that Porf-2, a neuron-expressed RhoGTPase-activating protein, plays an essential role in the inhibition of initial axon growth by restricting the expansion of the growth cone in a cell-autonomous manner. Furthermore, the EphB1 receptor is identified as an upstream controller that binds and regulates Porf-2 specifically upon extracellular ephrin-B stimulation. The activated EphB forward signal deactivates Rac1 through the GAP domain of Porf-2, which inhibits growth cone formation and brakes axon growth. Our results therefore provide a novel GAP that regulates axon growth and braking sequentially through Eph receptor-independent and Eph receptor-dependent pathways.
KeywordsAxon growth Porf-2 EphB GAP Vilse
Guanine nucleotide exchange factors
Preoptic regulatory factor-2
Short hairpin RNA
Cyclic adenosine monophosphate
Neural stem cell
Connector enhancer of KSR-2
Green fluorescent protein
Bovine serum albumin
We thank Prof. Jialin C. Zheng for providing the PDMS stamp model used in the stripe assay.
G-HH and LG designed and performed the experiments and wrote the manuscript. LZ, X-DL, Z-LS and H-JL performed the data and statistical analysis. N-JX and D-FF designed the experiments and revised the manuscript critically. All authors agree that all the questions related to the accuracy or integrity of the paper have been appropriately investigated and resolved and have given the final approval of the version to be published.
This study was supported by the National Natural Science Foundation of China (81772059 to D.-F.F, 31671062 and 31371097 to N.-J.X.), National Basic Research Program of China (Program 973 Grant 2014CB965002), 1000-Talents Program, Grants of Shanghai Brain-Intelligence Project from STCSM (16JC1420501), and the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (No. 2013-25) to N.-J.X.
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Conflict of interest
The authors declare that they have no conflict of interest.