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Neurofibromatosis type 1 (NF1) is one of the most prevalent dominantly inherited genetic diseases of the nervous system. NF1 encodes a tumor suppressor whose functional loss results in the development of benign neurofibromas that can progress to malignancy. Neurofibromas are complex tumors composed of axonal processes, Schwann cells, fibroblasts, perineurial cells, and mast cells. Through use of a conditional (cre/lox) allele, we show that loss of NF1 in the Schwann cell lineage is sufficient to generate tumors. In addition, complete NF1-mediated tumorigenicity requires both a loss of NF1 in cells destined to become neoplastic as well as heterozygosity in non-neoplastic cells. The requirement for a permissive haploinsufficient environment to allow tumorigenesis may have therapeutic implications for NF1 and other familial cancers.
Approximately 1 in 3500 individuals is born with a mutation in the NF1 gene and, because afflicted individuals can be long-lived, most mutations are retained within the population (1-3). The NF1 gene encodes neurofibromin, a protein of 2818 amino acids that harbors a functional Ras-GAP (guanosine triphosphatase activating protein) domain in its central region (4, 5). Neurofibromin is highly conserved among vertebrate species and has a 60% protein-wide homology with the Drosophila homolog (6).
The plexiform neurofibroma, thought to be embryonic in origin, can physically impede normal neurologic function. In addition, plexiform neurofibromas undergo transformation into malignant peripheral nerve sheath tumors, the most common malignancy associated with NFl (1-3, 7). It is unknown whether neurofibroma formation requires NF1 loss of heterozygosity (LOH) in a single cell type or in some specific complement of all the cell types commonly present in these tumors. A feature of NFI, as well as of other familial cancers, is that all nontumor tissue is heterozygous for the tumor suppressor. It is unknown whether tumor suppressor heterozygosity contributes to tumor formation or growth.
Chimeric analysis using NF1 homozygous (NF1^sup -/-^) embryonic stem cells has demonstrated that mice can develop tumors that resemble plexiform neurofibroma (8). These studies, however, did not address the identity of the cell types) that undergoes tumor initiation. To test the hypothesis that NF1 loss in Schwann cells is the genetic bottleneck for neurofibroma formation, we used a Cre transgene under control of the Krox20 promoter to ablate NFI function in these cells (9, 10). Analysis...