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

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.

Pathomechanisms in schwannoma development and progression

“…Genetic deletion of the nf2 gene has been shown to interfere with nerve regeneration in mice [ 2 , 27 – 29 ]. Both Mindos et al [ 27 ] and Truong et al [ 28 ] showed that mice bearing a Schwann cell-specific nf2 knockout exhibited a dramatic reduction of functional and morphological recovery after experimental sciatic nerve injury.…”

NEDD4L‐mediated Merlin ubiquitination facilitates Hippo pathway activation

“…Merlin mutations have also been associated with sporadic tumors, such as schwannomas, meningiomas, malignant mesotheliomas, and thyroid carcinomas (Cooper & Giancotti, 2014;Petrilli & Fernandez-Valle, 2016). In addition to its tumor suppressor functions, Merlin is important for maintaining neuron organization and integrity as well as regulating nerve regeneration after damage (Schulz et al, 2013(Schulz et al, , 2016Mindos et al, 2017;Toledo et al, 2019). Recent studies have made significant progress toward understanding Merlin's molecular functions, but it remains unclear how Merlin is activated in response to growth suppressive cues or other signals.…”

Targeted massively parallel sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas: An analysis of 51 individuals in a single‐center experience

“…Furthermore, a different NEFH missense variant, c.1582G>C (p.Ala528Pro), not reported in the gnomAD database cohort, has been found in an individual with a sporadic schwannoma from the independent cohort from Agnihotri et al (2016) (Table ). To our knowledge, there is no published evidence on any association between this gene and schwannomas, except that the NEFH promotor is usually used to drive Cre recombinase activity (Nefh Cre) to obtain the Nf2 knockout mouse model (Schulz et al, 2016). Besides, the constitutional hemizygous NF2/NEFH codeletion has been found in three NF2‐affected individuals with very mild phenotypes, although no clinical details were provided (Watson et al, 1993).…”