Neurofibromatosis Type 1 and Type 2 (NF1 and NF2) are phenotypically related yet genotypically distinct cancers of the nervous system which share the proliferation of Schwann cells adjacent to the spinal cord. Thus, the dorsal root ganglion (DRG) and associated nerve root are an active locus of Schwann cell proliferation in both NF1 and NF2 and provides an ideal location to study mechanisms shared by the Neurofibromatoses. Administration of nerve growth factor (NGF) results in abnormal proliferation of Schwann and satellite cells within and adjacent to the DRG. Long-term infusion in rats leads to Schwann cell hyperplasia that invades the central nervous system similar to hamartomas in NF. Infusion of NGF for 2 weeks results in a massive increase in Schwann cells detected by using bromodeoxyuridine (BrdU) to label dividing cells. Quantitative assessment of proliferation with BrdU immunohistochemistry using unbiased stereology indicates a greater than 2-fold increase in Schwann cells in the trigeminal ganglia and DRG. This proliferation models one aspect of both NF1 and NF2 and thus may serve as a novel method to quantitatively assess the role of different growth factors receptor signaling cascades in tumor progression. The underlying theme of this proposal is that growth factor induced proliferation of peripheral glia cells offers a model of Schwann cell tumors found in NF1 and NF2. Using quantitative immunohistochemical methods, the signaling cascades, which regulate glia proliferation, can be investigated in an in vivo model. To study growth factor-induced Schwann cell proliferation as a quantitative model of the neurofibromatoses, three aims are proposed: 1) identify which receptor system of the growth factors is critical for Schwann cell proliferation by comparing infusions of different neurotrophins (NT) and secondly by infusing the optimal NT in NT receptor knockout mice, 2) determine the molecules involved in tumor development and the CNS invasion of these cells by combining infusions of NT and meningeal cell mitogens, and in parallel profiling molecules involved in breach of the CNS, and 3) investigate second messenger systems wherein neurotrophin receptors signals impinge upon either merlin or neurofibromin by infusing NT into NF1 or NF2 transgenic mice, and secondly by administering inhibitors of the growth factor cascades. These studies will elucidate the mechanisms and signaling pathways through which growth factors play a role in Schwann cell proliferation and impinge upon the proteins mutated in NF1 and NF2. Furthermore, the development of a quantitative tumor model allows for the assessment of small molecule therapeutics in a pre-clinical setting. ? ?
| Schlachetzki, Johannes C M; Pizzo, Donald P; Morrissette, Debbi A et al. (2014) Intracerebroventricular administration of nerve growth factor induces gliogenesis in sensory ganglia, dorsal root, and within the dorsal root entry zone. Biomed Res Int 2014:704259 |
