Early Inhibition of the MAPK Pathway Prevents Optic Nerve Glioma Formation in a Nf1-Deficient Mouse Model

[摘要] Low-grade pilocytic astrocytomas are the most common type of glioma found in children. Children with the inherited tumor predisposition syndrome, Neurofibromatosis type 1 (NF1), are especially prone to develop optic pathway gliomas (OPGs) primarily involving the anterior visual pathway composed of the optic nerve, chiasm and tracts. These tumors usually manifest in patients younger than 7 years of age, with the peak incidence between years 4 and 5. Despite the benign nature of these tumors, a subset of OPGs will develop and cause vision loss and other endocrine problems. Although treatment with non-alkylating chemotherapeutic agents has resulted in efficient disease stabilization, their ability to maintain or improve vision remains unclear. Despite recent advances in understanding how NF1 regulates neural stem and glial precursor cells in the brain, it remains uncertain which cell population(s) is (are) most affected by Nf1 loss in OPGs. In addition, there is urgent need to define therapeutic windows to develop effective preventative and therapeutic strategies before visual deterioration.This thesis focuses on understanding the timing and mechanism(s) of how loss of Nf1 contributes to the formation of OPG by using a genetically engineered mouse (GEM) model of NF1-OPG.In this model, Nf1 was inactivated in neural stem and progenitor cell populations during embryonic development. The resulting mutant pups (Nf1hGFAPCKO) display hyperplastic lesions in the prechiasmatic optic nerves that develop into OPGs with high penetrance. A detailed analysis of the natural history of OPGs in Nf1hGFAPCKOs yielded several important findings. Nf1 loss in the developing optic nerve leads to the expansion of an abnormal glial cell population that expresses both GFAP and Olig2, and over-activates RAS/MEK/ERK signaling as well as glia restricted progenitor cells which, persist throughout gliomagenesis. Importantly, MEKi treatment during a critical developmental window (P0.5-P21) is sufficient to prevent the formation of OPG in Nf1hGFAPCKO mice and rescue retinal ganglion cells (RGC) loss. Likewise, genetic inactivation of Mek1/2 rescues the formation of OPG and the death of RGCs in a dose-dependent manner. Collectively, this study clearly demonstrates that OPGs are a developmental defect with Erk-dependent glial cell expansion occurring during the early postnatal period (Phase I) followed by an immune response, nerve degeneration and Bax-mediated RGC apoptosis (Phase II) and identifies a critical period for neuroprotective intervention before irreversible neurological deficits. Lastly, we have developed a preclinical model to test for the biological effects of MEK inhibitor-based preventative therapies, which allows us to screen for the optimal dose and delivery method.

[发布机构] University of Michigan

[效力级别] Science (General)

[关键词] NF1-OPG;Science (General);Science;Neuroscience