Rab8a/Rab11a regulate intercellular communications between neural cells via tunneling nanotubes.

Hui Zhu,Jingjing Lu,Chengbin Xue,Xiaohong Li,Yibing Guo,Yongjun Wang,Zheng Cao,Xi Xu,Xiaosong Gu,Shaoqing Ju

doi:10.1038/cddis.2016.441

Abstract

Tunneling nanotubes (TNTs) are F-actin-based membrane tubes, and can form between cultured cells and within vital tissues. TNTs mediate intercellular communications that range from electrical signaling to the transfer of organelles. Following peripheral nerve injury, the orchestrated intercellular communications among neural and non-neural cells are required for effective nerve regeneration. It remains unknown whether TNTs exist between neural cells in the peripheral nerve system and how TNTs affect neural regeneration. To address these interesting questions, we investigated the transfer of neurotropic factors, membrane protein, cytoplasmic protein, mitochondria and RNA in functional TNTs formed between cultured Schwann cells (SCs). TNT-like structures were increased not only in cultured SCs after exposure to serum depletion but also in longitudinal sections of proximal sciatic nerve stump harvested after rat peripheral nerve transection. Meanwhile, downregulation of Rab8a or Rab11a in cultured SCs inhibited the formation of functional TNTs and vesicle transfer and led to decrease in cell migration, increase in SCs apoptosis. Likewise, knockdown of Rab8a or Rab11a in primary SCs also suppressed axonal outgrowth from co-cultured dorsal root ganglion (DRG) neurons. Overall, our results suggested that the gene of Rab8a or Rab11a might be involved in the formation of TNTs structures in the peripheral nerve system, while TNTs structures were likely to affect peripheral nerve regeneration through the regulation of neural cell communications.

Highlights

IntroductionGrowing evidence for the intercellular transfer of molecules as large as proteins and cytoplasmic components through synapse, gap junctions, and tunneling nanotubes (TNTs) in aspect of tissue repair, immune response, cancer, normal tissue homeostasis and osteoclastogenesis has been reported.[1,2,3,4,5,6] As an nanoscaled, F-actin containing long membrane protrusions, TNTs facilitate the intercellular communication of diverse cellular signals and components ranging from electrical signaling to organelles.[5,7,8,9] Intercellular communication is related to many diseases and nanotubes are potentially useful as drug-delivery channels for cancer therapy
The occurrence of tunneling nanotubes (TNTs) has been observed in many cell types in vitro, it remains to be determined whether the TNTs transfer mechanisms and their cargos are cell-type specific.[5]
In central nervous system (CNS), donor neurons overloaded with α-synuclein aggregates were recently reported as a mechanism of hijacking TNT-mediated intercellular trafficking to the neighbor cells which may contribute to the neuropathology—Parkinson’s disease.[10]

Summary

Introduction

Growing evidence for the intercellular transfer of molecules as large as proteins and cytoplasmic components through synapse, gap junctions, and tunneling nanotubes (TNTs) in aspect of tissue repair, immune response, cancer, normal tissue homeostasis and osteoclastogenesis has been reported.[1,2,3,4,5,6] As an nanoscaled, F-actin containing long membrane protrusions, TNTs facilitate the intercellular communication of diverse cellular signals and components ranging from electrical signaling to organelles.[5,7,8,9] Intercellular communication is related to many diseases and nanotubes are potentially useful as drug-delivery channels for cancer therapy. The communication and interactions between Schwann cells (SCs) and neurons are critical for the development and function of myelinated axons.[12] Such interactions take place during development and in adulthood, and are critical for the homeostasis of the peripheral nervous system (PNS). Deregulation of neuron-SC interactions often results in developmental abnormalities and diseases.[13] Neurons and SCs exist in a highly interdependent relationship: damage to one cell type usually leads to pathophysiological changes in the other.[14] Peripheral nerve injury (PNI) as a global clinical problem causes a devastating impact on patients’ quality of life.[15,16] the PNS has a greater capacity of axonal regeneration than the CNS after injury, spontaneous repair of peripheral nerve is nearly always unsatisfied with poor functional recovery. Cell Death and Disease to our understanding of the development, physiology and pathology of the peripheral nervous system as a whole

Methods

Results

Conclusion