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Updated: Jul 17, 2026
An Orthotopic Sciatic Nerve Xenograft for Neurofibromatosis Type 1 Neurofibromas
Published on: October 10, 2025
Conditional N-rasG12V expression promotes manifestations of neurofibromatosis in a mouse model
H Saito1, T Yoshida, H Yamazaki
1Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, Edobashi, Tsu, Mie, Japan.
Abstract:
Human clinical neurofibromatosis type 1 (NF1) and type 2 (NF2) result from mutations and inactivation of neurofibromin and merlin genes, respectively, which negatively regulate Ras pathways. To evaluate the contribution of N-Ras activity to the development of NF, we generated a novel transgenic mouse expressing oncogenic N-ras specifically in central nerve cells, neural crest-derived cells and lens epithelial cells. Soon after birth, the mouse skin showed hyperpigmentation of the epidermis and melanin-laden macrophages in the dermis, as observed in the café-au-lait spots of human cases. At 3 months of age, all the mice had neurofibromas in the skin and neurofibroma-like tumors with structure similar to Wagner-Meissner bodies in the adrenal medulla. At 4 months of age, all the mice developed subcapsular cataract. In the 5th month, some developed protruding dermal neurofibromas involving subcutaneous fat. However, plexiform neurofibroma, schwannoma, astrocytoma and pheochromocytoma were not observed in the mice, suggesting a requirement for signal(s) other than the activated N-Ras pathway to induce these tumors. Thus, the activated N-Ras signal may be a main pathway for the development of the disease phenotypes characteristic of NF.
Insights
Activating N-Ras in mice caused neurofibromatosis-like skin and adrenal tumors, mimicking human NF1 symptoms. This suggests N-Ras pathway activation is key to developing neurofibromatosis phenotypes.
Area of Science:
- Genetics
- Oncology
- Developmental Biology
Background:
- Neurofibromatosis types 1 and 2 (NF1, NF2) arise from mutations in tumor suppressor genes (neurofibromin, merlin) that regulate Ras pathways.
- Understanding the role of Ras pathway activation in NF pathogenesis is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the specific contribution of N-Ras pathway activation to the development of neurofibromatosis phenotypes.
- To establish a novel mouse model for studying NF pathogenesis.
Main Methods:
- Generation of a transgenic mouse model expressing oncogenic N-ras in neural crest-derived cells, central nerve cells, and lens epithelial cells.
- Observation and characterization of phenotypic manifestations in the N-ras transgenic mice from birth to 5 months of age.
Main Results:
- Transgenic mice exhibited café-au-lait spots and dermal neurofibromas, mirroring human NF1 clinical presentations.
- Neurofibroma-like tumors were found in the adrenal medulla, and subcapsular cataracts developed by 4 months.
- Absence of plexiform neurofibroma, schwannoma, astrocytoma, and pheochromocytoma suggests other signaling pathways are involved in these specific tumor types.
Conclusions:
- Activated N-Ras signaling is a significant driver for key neurofibromatosis phenotypes observed in this model.
- Further research is needed to identify cooperating signals required for the development of specific NF-associated tumors.
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