Perinatal or Adult Nf1 Inactivation using Tamoxifen-inducible PlpCre Each Cause Neurofibroma Formation
1Mayes DA, 1Rizvi TA, 1,3Cancelas JA, 1Kolasinski N, 2Ciraolo CM, 4Stemmer-Rachamimov AO, and 1Ratner N
Divisions of 1Experimental Hematology and Cancer Biology, and 2Pathology, Cincinnati Children’s Hospital Medical Center, 3Hoxworth Blood Center, University of Cincinnati, Department of Pathology4, Massachusetts General Hospital and Harvard Medical School.
OBJECTIVES
Neurofibromas are tumors initiated by biallelic mutation of the NF1 tumor suppressor gene in the Schwann cell lineage. One idea within the field suggests that Nf1 loss must occur within progenitor cells present within a critical window during Schwann cell development in order for neurofibromas to form. To test this hypothesis and to examine whethermyelinating Schwann cells can serve as aneurofibroma cell of origin, Nf1 loss was induced at perinatal or adult timepoints using a tamoxifen-inducible Plp-CreERT driver.
RESULTS
Perinatal loss of Nf1 resulted in small neurofibromas late in life, while adult loss caused large neurofibromas and morbidity beginning 4 months after onset of Nf1 loss. PLP-CreERT recombination (EGFP+ cells) occurred in: satellite cells, S100β+ myelinating Schwann cells, and p75+ cells. Plp-CreERTnerves and neurofibromas contained cells with Remak bundle disruption; however, no recombination within GFAP+ non-myelinating Schwann cells was identified. Extramedullarylympho-hematopoietic expansion that contained EGFP+/Sca-1+ stromal cells amongst EGFP-negative lympho-hematopoietic cells was also observed.
CONCLUSIONS/SIGNIFICANCE
Neurofibroma formation is not restricted to loss of Nf1 in embryonic life, but can be triggered by Nf1 loss throughout life.Although all neurofibroma models and human samples have Remak bundle disruption (leading to the assumption that Nf1 loss within the non-myelinating Schwann cell may be vital for tumor formation), there was no EGFP+ recombination within GFAP+ non-myelinating Schwann cells – eliminating the GFAP+ non-myelinating Schwann cell as the cell of origin for neurofibroma formation.
SUPPORTED BY: This work was supported by an NIH NRSA (T32CA117846) and the National Multiple Sclerosis Society (FG1762A1/1) Postdoctoral Fellowships to D.A.M and the DAMD Program on Neurofibromatosis (W81XWH-06-1-0114 to T.A.R. and N.R.) and NIH R01-NS28840 (NR).
