Abstract
While most children develop cancer without a clear etiology, some pediatric cancers arise in the context of tumor predisposition syndromes, typically caused by germline mutations in genes that regulate cell growth. The most common of these syndromes, Neurofibromatosis type 1 (NF1), affects ~1:3,000 individuals worldwide, 15% of whom will develop low-grade tumors of the optic pathway (optic pathway gliomas; OPGs). However, it is currently unclear which children with NF1 will develop an OPG, making risk assessment for each individual child difficult. Recent evidence suggests that the specific NF1 germline mutation that each child is born with may be one factor that modulates tumor penetrance. To address the hypothesis that specific germline NF1 gene mutations differentially increase the risk of optic glioma formation through cell-intrinsic effects on the tumor cell of origin, we designed a series of studies to examine the impact of different NF1 germline gene mutations on neuroglial progenitor cell populations in the developing brain. We first defined the putative cells of origin – neuroglial progenitor cells within the third ventricular zone (TVZ) – over normal mouse brain development using Nestin-CFPnuc reporter mice. Three cell populations were identified, and these populations display distinct spatial localizations and are dynamic over the course of late embryonic and early postnatal development. Functional differences were identified between these populations in vitro (e.g., differential clonogenic incidence and proliferation), and additional differences were identified by RNA sequencing. After characterizing these populations, we evaluated their spatiotemporal dynamics in mice genetically engineered to harbor different NF1 patient-derived germline Nf1 gene mutations. Interestingly, some, but not all, Nf1 gene mutations resulted in increased GFAP+ progenitor content and progenitor proliferation. Taken together, these findings provide early experimental evidence for mutational specificity in specific putative brain tumor cells of origin relevant to glioma penetrance.
NF1 Gene Mutations Represent the Major Molecular Event Underlying Neurofibromatosis-Noonan Syndrome