Voltage-dependent membrane currents of cultured human neurofibromatosis type 2 Schwann cells

Hemizygosity for the NF2 gene in humans causes a syndromic susceptibility to schwannoma development. However, Nf2hemizygous mice do not develop schwannomas but mainly osteosarcomas. In the tumors of both species, the second Nf2 allele is inactivated. We report that conditional homozygous Nf2 knockout mice with Cre-mediated excision of Nf2 exon 2 in Schwann cells showed characteristics of neurofibromatosis type 2. These included schwannomas, Schwann cell hyperplasia, cataract, and osseous metaplasia. Thus, the tumor suppressor function of Nf2, here revealed in murine Schwann cells, was concealed in hemizygousNf2 mice because of insufficient rate of second allele inactivation in this cell compartment. The finding of this conserved function documents the relevance of the present approach to model the human disease.

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Isolation and Characterization of Schwann Cells from Neurofibromatosis Type 2 Patients

Neurobiology of Disease ◽

10.1006/nbdi.1998.0179 ◽

1998 ◽

Vol 5 (1) ◽

pp. 55-64 ◽

Cited By ~ 46

Author(s):

C. Rosenbaum ◽

L. Kluwe ◽

V.F. Mautner ◽

R.E. Friedrich ◽

H.W. Müller ◽

...

Keyword(s):

Schwann Cells ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Isolation And Characterization

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Activation of Raf signalling in NF2-null Schwann cells leads to sustained proliferation; an investigation of a new and inducible model for human schwannoma

Neuro-Oncology ◽

10.1093/neuonc/noab195.013 ◽

2021 ◽

Vol 23 (Supplement_4) ◽

pp. iv7-iv7

Author(s):

Charlotte Lespade ◽

Liyam Laraba ◽

Evyn Woodhouse ◽

Marie Srotyr ◽

Alison C Lloyd ◽

...

Keyword(s):

Schwann Cell ◽

Mouse Model ◽

Schwann Cells ◽

Nerve Injury ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Proliferation Response

Abstract Aims The NF2 gene encodes the tumour suppressor Merlin, which is deleted in 100% of patients with the familial tumour predisposition syndrome neurofibromatosis type 2 but also in 70% of those who develop sporadic schwannomas. The Raf-TR mouse model uses a tamoxifen-inducible Raf-kinase/ oestrogen receptor fusion protein (Raf-TR) expressed in myelinating Schwann cells to mimic a nerve injury response in Schwann cell by activating Raf/MEK/ERK signalling in the absence of peripheral nerve injury. We will assess whether Raf/MEK/ERK activation on an NF2 null background leads to tumourigenesis within the vestibular nerves and dorsal root ganglia (DRGs), two tumour sites identified in the Periostin-Cre mouse model in which schwannoma formation is spontaneous, with a view to generating an inducible NF2 null schwannoma mouse model. Method Mice with a Schwann cell specific loss of Merlin were crossed with mice carrying a tamoxifen-inducible Raf-TR gene to generate Raf-TR+/-; P0-Cre+/-; NF2fl/fl (Cre+) mice which were NF2 null and compared to Raf-TR+/-; P0-Cre-/-; NF2fl/fl (Cre-) littermate controls. Mice were injected with tamoxifen or vehicle for five consecutive days and their vestibular nerves and dorsal root ganglia (DRGs) were analysed at various timepoints . An EdU proliferation assay was used to quantify the proliferation in the vestibular ganglia, as well as the DRGs. Rates of proliferation were compared to Cre- age-matched littermate controls treated with tamoxifen or vehicle. Results In the Periostin-Cre NF2 null schwannoma model, tumours form spontaneously in the DRGs and vestibular ganglia. In our new model, we see a clear increase in proliferation at 21 d post-injection in the NF2 null (Cre+) tamoxifen-treated mice compared to control (Cre-) tamoxifen-treated controls in both DRGs and vestibular ganglia. Cre- tamoxifen-treated mice do not show increased proliferation compared to Cre- vehicle controls. Taken together, this shows that activation of the Raf/MEK/ERK pathway in Schwann cells only causes a sustained proliferation response on an NF2 null background in the DRGs and vestibular ganglia. We are assessing later timepoints to further characterise tumour development in these mice. Conclusion Combining the Raf-TR mouse model to create a demyelinating phenotype with an NF2 null background leads to vastly increased rates of proliferation at the sites of schwannoma tumourigenesis within the peripheral nervous system: the DRGs and the vestibular ganglia. The high proliferation in the vestibular ganglia in particular is similar to the development of vestibular schwannomas in patients with Neurofibromatosis type 2. The new mouse model used in this study shows potential to be very useful as an inducible schwannoma tumour model, in which we can study the early events of tumour formation.

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