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Developmental Biology - Nerve Regeneration

How Schwann Cells Repair Axons

Injured axons instruct Schwann cells to regenerate...

Damaged peripheral nerves can regenerate after an injury, for example, following a forearm fracture. Axons, the long projections of neurons that transmit stimuli (signals) to other cells, damaged through injury - need to regrow to recover their function.

Now, a research team led by professor Claire Jacob PhD, head of the Cellular Neurobiology Group at Johannes Gutenberg University Mainz since October 2018, investigating this repair process finds the same mechanism can be activated even in cells of the central nervous system - after spinal cord injury. The article, published in Cell Reports, includes findings from the research groups at the Universities of Fribourg (Switzerland) and Mainz.
"An injury in the peripheral nervous system quickly triggers the activation of a fascinating repair process that allows an injured nerve to regenerate and regain function. There [was thought] to be no such repair process in the central nervous system, thus injuries often lead to permanent damage such as paraplegia."

Claire Jacob PhD, Head of the Cellular Neurobiology Group, Fribourg, Switzerland; Department of Biology, Johannes Gutenberg University, Mainz, Germany.

Myelin-forming cells are key to the axon regeneration process. Many axons are sheathed in myelin, which serves as a protective cell layer also enabling fast and efficient signal transmission. "Myelin is extremely important for the function of the entire nervous system, however it can hinder repair in cases of injury," adds Jacob.

Myelin is produced by Schwann cells in the peripheral nervous system and by oligodendrocytes in the central nervous system — a difference with major impact on axon regeneration as Schwann cells and oligodendrocytes respond very differently to axon injury.

Schwann cells can break down myelin + damaged axons

When axons of the peripheral nervous system are injured, Schwann cells rapidly induce disintegration of the injured axonal segments into small fragments. These fragments can then be digested either by Schwann cells themselves, or later by macrophage cells. This elimination of axonal debris is a critical first step in the repair process.
"Schwann cells can do everything. We discovered that they not only digest myelin following injury, but also induce disintegration of long axon segments separated from cell bodies due to injury."

Claire Jacob PhD.

The process begins when Schwann cells form small spheres made up of a protein called actin. Actin spheres then exert pressure on any isolated axon segment until it disintegrates. This targeted degradation of cell debris is essential to enable healthy axon parts remain attached to the neuron cell body. This allows for regeneration by undamaged cells and reconnection to an axon's former target, restoring full nerve signal transmission.
Jacob's team identified that severed pieces of axons send signals to Schwann cells beginning actin sphere formation.

If this impressive and precisely coordinated interaction between two cell types is disrupted, axon disintegration slows down and fragments impair regeneration in damaged nerves.

Manipulated oligodendrocytes can generate actin structures

Claire Jacob's team then went on to study the response of the central nervous system oligodendrocytes. Oligodendrocytes do not (normally) form actin spheres, as Schwann cells do, and cannot break down axon segments. Jacob: "After an injury, oligodendrocytes either die or remain unresponsive."
Unlike Schwann cells, oligodendrocytes do not express VEGFR1, a receptor triggering production of actin spheres as seen done by Schwann cells.

Therefore researchers induced expression of VEGFR1 from oligodendrocytes.

The result: oligodendrocytes produced actin spheres, disintegrated axon fragments and promoted central nervous system nerve regeneration at injured sites.

The team is currently identifying each process the central nervous system will need to repair injuries. Myelin removal is a second prerequisite to disposal of axon debris before any neuron regeneration can begin.
"We have discovered a pathway that accelerates myelin degradation in the peripheral nervous system — and are now trying to determine whether this can also trigger myelin removal in the central nervous system."

Claire Jacob PhD.

• Injured axons upregulate PlGF, which activates VEGFR1 in Schwann cells
• VEGFR1 activates the formation of constricting actin spheres in Schwann cells
• Constricting actin spheres accelerate the disintegration of injured axons
• VEGFR1 expression in oligodendrocytes accelerates injured axon disintegration

After a peripheral nerve lesion, distal ends of injured axons disintegrate into small fragments that are subsequently cleared by Schwann cells and later by macrophages. Axonal debris clearing is an early step of the repair process that facilitates regeneration. We show here that Schwann cells promote distal cut axon disintegration for timely clearing. By combining cell-based and in vivo models of nerve lesion with mouse genetics, we show that this mechanism is induced by distal cut axons, which signal to Schwann cells through PlGF mediating the activation and upregulation of VEGFR1 in Schwann cells. In turn, VEGFR1 activates Pak1, leading to the formation of constricting actomyosin spheres along unfragmented distal cut axons to mediate their disintegration. Interestingly, oligodendrocytes can acquire a similar behavior as Schwann cells by enforced expression of VEGFR1. These results thus identify controllable molecular cues of a neuron-glia crosstalk essential for timely clearing of damaged axons.

Adrien Vaquié, Alizée Sauvain, Mert Duman, Gianluigi Nocera, Boris Egger, Felix Meyenhofer, Laurent Falquet, Luca Bartesaghi, Roman Chrast, Christophe Maurice Lamy, Seokyoung Bang, Seung-Ryeol Lee, Noo Li Jeon, Sophie Ruff and Claire Jacob.

Plp-CreERT2 mice have been used in collaboration with Dr. Ueli Suter. We thank Dr. Edward M. Callaway for the pLV-LSyn-RFP construct, Dr. Olivier Pertz for the LifeAct-GFP construct, Dr. Jacqueline Trotter for the Oli-neu cell line, Dr. Frank Pfrieger for comments on the manuscript, and the Lausanne Genomic Technologies Facility of the University of Lausanne for the RNA sequencing. C.J. acknowledges support from the Swiss National Science Foundation (grants PP00P3_1139163, PP00P3_163759, and 31003A_173072), the International Foundation for Research in Paraplegia, OPO-Stiftung (grant IRP-P147), and the Novartis Foundation for Medical-Biological Research (grant 15C191). N.L.J. acknowledges support from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and Technology (NRF 2018R1A2A1A05019550).

Claire Jacob is the head of the Cellular Neurobiology Group at Johannes Gutenberg University Mainz since October 2018. The article, published in Cell Reports, includes findings from the research groups at the Universities of Fribourg (Switzerland) and Mainz. In September 2018, Claire Jacob was awarded the prestigious IRP Schellenberg Research Prize.

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Jul 15 2019   Fetal Timeline   Maternal Timeline   News  

Actin spheres (GREEN) wrap around injured axon (RED) digesting broken fragments and provide sheathing to conduct signals between intact axon cells. Videos of each stage of axon regeneration can be viewed online at Cell Reports. CREDIT Johannes Gutenberg University Mainz.

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