A Transgenic Mouse Model for Human Neurofibromatosis

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) has been associated with the neurologic disorder tropical spastic paraparesis and possibly with multiple sclerosis. The tat gene of HTLV-1 under control of its own long terminal repeat is capable of inducing tumors in transgenic mice. The morphologic and biologic properties of these tumors indicate their close resemblance to human neurofibromatosis (von Recklinghausen's disease), the most common single gene disorder to affect the nervous system. The high spontaneous incidence of this disease, together with the diverse clinical and pathologic features associated with it, suggests that environmental factors may account for some of the observed cases. Multiple tumors developed simultaneously in the transgenic tat mice at approximately 3 months of age, and the phenotype was successfully passed through three generations. The tumors arise from the nerve sheaths of peripheral nerves and are composed of perineural cells and fibroblasts. Tumor cells from these mice adapt easily to propagation in culture and continue to express the tat protein in significant amounts. When transplanted into nude mice, these cultured cells efficiently induce tumors. Evidence of HTLV-1 infection in patients with neural and other soft tissue tumors is needed in order to establish a link between infection by this human retrovirus and von Recklinghausen's disease and other nonlymphoid tumors.

Tax1 enhances cancer cell proliferation via Ras–Raf–MEK–ERK signaling pathway

“…It is reported that Tax1 transforms the primary lymphocytes and rat fibroblasts in vitro (30,31). The oncogenic properties of the protein in vivo were confirmed in the transgenic mouse models, in which a range of malignant disorders including mesenchymal tumors, neurofibro- mas, and large granular lymphocytic leukemia were developed (30)(31)(32). The transformation properties of Tax1 are a consequence of the ability to deregulate the gene transcription and signal transduction in the processes of cell proliferation, cell cycle control, and apoptosis.…”

A 36-kilodalton cellular transcription factor mediates an indirect interaction of human T-cell leukemia/lymphoma virus type I TAX1 with a responsive element in the viral long terminal repeat.

“…The transforming potential of these proteins has been illustrated by their ability to immortalize primary T lymphocytes (21,53). In addition, transgenic mice carrying the TAX, gene develop neurofibromas (28,47). In addition to viral genes, TAX1 (previously known as x-lor, p40x, and tat1; 18) has also been shown to transactivate certain cellular genes (3,17,29,38,44,46,56).…”

Mutational analysis of the HTLV‐Itrans‐activator, Tax

“…Tax is regarded as the transforming agent of HTLV-I, leading to adult r-cell leukemia [4][5][6]. Beyond its intracellular function as a transcriptional regulator, extraeellular Tax protein also affects lymphoid cells [7].…”