Neuron-Specific Deletion of the Nf2 Tumor Suppressor Impairs Functional Nerve Regeneration.

Alexander Schulz,Robert Büttner,Helen Morrison,Stephan L Baader,Andrey Irintchev,Julia Von Maltzahn,Reinhard Bauer,Andrea Toledo

doi:10.1371/journal.pone.0159718

Abstract

In contrast to axons of the central nervous system (CNS), axons of the peripheral nervous system (PNS) show better, but still incomplete and often slow regeneration following injury. The tumor suppressor protein merlin, mutated in the hereditary tumor syndrome Neurofibromatosis type 2 (NF2), has recently been shown to have RhoA regulatory functions in PNS neurons—in addition to its well-characterized, growth-inhibitory activity in Schwann cells. Here we report that the conditional knockout of merlin in PNS neurons leads to impaired functional recovery of mice following sciatic nerve crush injury, in a gene-dosage dependent manner. Gross anatomical or electrophysiological alterations of sciatic nerves could not be detected. However, correlating with attenuated RhoA activation due to merlin deletion, ultrastructural analysis of nerve samples indicated enhanced sprouting of axons with reduced caliber size and increased myelination compared to wildtype animals. We conclude that deletion of the tumor suppressor merlin in the neuronal compartment of peripheral nerves results in compromised functional regeneration after injury. This mechanism could explain the clinical observation that NF2 patients suffer from higher incidences of slowly recovering facial nerve paralysis after vestibular schwannoma surgery.

Highlights

The successful regeneration of damaged nerve cells due to traumatic injuries or neurodegenerative conditions, displays a desirable, if not yet realistic therapeutic goal
While axons of the central nervous system (CNS) are mostly incapable of sufficient regeneration, axons of the peripheral nervous system (PNS) generally show a remarkable repair response—due to strong intrinsic growth capacity coupled with permissive environmental factors [1]
In order to study the role of the tumor suppressor protein merlin in peripheral nerve regeneration in vivo, mice with a cell type-specific loss of merlin in neurons underwent a defined study protocol (Fig 1a)

Summary

Introduction

The successful regeneration of damaged nerve cells due to traumatic injuries or neurodegenerative conditions, displays a desirable, if not yet realistic therapeutic goal. While axons of the CNS are mostly incapable of sufficient regeneration, axons of the PNS generally show a remarkable repair response—due to strong intrinsic growth capacity coupled with permissive environmental factors [1]. Several molecular targets have been identified that stimulate neuron-intrinsic capabilities to either regenerate or overcome myelin-associated. Small GTPases—and in particular RhoA signals—have proven to be key regulators of both neuromorphogenesis during development and regeneration of the nervous system by local cytoskeleton rearrangements [3]. Inhibition of RhoA and its downstream kinase ROCK (Rho-associated kinase), has been shown to enhance nerve regeneration in the peripheral nervous system [6]. Activity regulators of small G-proteins such as RhoA present as promising targets for interfering with the regenerative capacity of neurons

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Conclusion