Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation.

Debra A Mayes,Anat O Stemmer-Rachamimov,Tilat A Rizvi,Nancy Ratner,Georgianne M Ciraolo,Nathan T Kolasinski,Jose A Cancelas

doi:10.1158/0008-5472.can-10-4558

Abstract

Plexiform neurofibromas are peripheral nerve sheath tumors initiated by biallelic mutation of the NF1 tumor suppressor gene in the Schwann cell lineage. To understand whether neurofibroma formation is possible after birth, we induced Nf1 loss of function with an inducible proteolipid protein Cre allele. Perinatal loss of Nf1 resulted in the development of small plexiform neurofibromas late in life, whereas loss in adulthood caused large plexiform neurofibromas and morbidity beginning 4 months after onset of Nf1 loss. A conditional EGFP reporter allele identified cells showing recombination, including peripheral ganglia satellite cells, peripheral nerve S100β+ myelinating Schwann cells, and peripheral nerve p75+ cells. Neurofibromas contained cells with Remak bundle disruption but no recombination within GFAP+ nonmyelinating Schwann cells. Extramedullary lympho-hematopoietic expansion was also observed in PlpCre;Nf1fl/fl mice. These tumors contained EGFP+/Sca-1+ stromal cells among EGFP-negative lympho-hematopoietic cells indicating a noncell autonomous effect and unveiling a role of Nf1-deleted microenvironment on lympho-hematopoietic proliferation in vivo. Together these findings define a tumor suppressor role for Nf1 in the adult and narrow the range of potential neurofibroma-initiating cell populations.

Highlights

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disease, affecting approximately 1:3000 individuals worldwide [1]
Loss of Nf1 in animal models using neural crest drivers Wnt1-Cre (E9.5), Mpz–Cre (E9.5–10.5), and Pax3–Cre (E10.5) did not result in neurofibroma formation [21]. These findings suggested that a post-crest target cell(s) drives neurofibroma formation; several laboratories targeted Nf1 loss to Schwann cell populations after neural crest migration
Littermate PlpCre; Nf1wt controls remained healthy. On gross dissection these PlpCre;Nf1fl/fl animals had enlarged peripheral nerves associated with paraspinal tumors at cervical (Fig. 1B) and thoracic spinal levels

Summary

Introduction

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disease, affecting approximately 1:3000 individuals worldwide [1]. Schwann cells differentiate in close association with the axons of peripheral nerves. Loss of Nf1 in animal models using neural crest drivers Wnt1-Cre (E9.5), Mpz–Cre (E9.5–10.5), and Pax3–Cre (E10.5) did not result in neurofibroma formation [21]. These findings suggested that a post-crest target cell(s) drives neurofibroma formation; several laboratories targeted Nf1 loss to Schwann cell populations after neural crest migration. Peripheral nerve Remak bundles containing small diameter axons ensheathed by a single Schwann cell are disrupted in all neurofibroma models. This led to the suggestion that nonmyelinating Schwann cell are tumor-initiating cells within neurofibromas [23]. While Remak bundle disruption is shown within the neurofibromas, GFAPþ nonmyelinating Schwann cells do not show Nf1 inactivation

Materials and Methods

Results

Discussion

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