This Project pursues recent advances in the cell biology of medulloblastomas (MBs) and related central nervous system (CNS) primitive neuroectodermal tumors (PNETs) by studying neurotrophins and their cognate receptors (trkA, trkB or trkC) to gain insights into the role of neurotrophins in the progression of these common pediatric brain tumors. MB cells resemble immature CNS neurons or their progenitors, and MBs primarily occur in the first decade of life when heterotopic immature neurons and/or neuroectodermal progenitor cells are most abundant in cerebellum where most MBs arise. The relevant CNS neurotrophins that might regulate the behavior of neuroectodermal progenitors as well as MBs and PNETs are nerve growth factor (NGF) and related neurotrophins, i.e. brain derived neurotrophic factor (BDNF), NT3 and NT4/5. These factors bind to the low affinity NGF receptor (LNGFR), but the effects of NGF, BDNF NT3 and NT4/5 are thought to be mediated primarily by high affinity receptors, i.e.. trkA (NGF, NT4/5), trkB (BDNF, NT4/5) or trkC (NT3). Studies from our laboratory indicate that trk receptor proteins are expressed in the developing and mature human cerebellum, and that MBs, PNETs and cell lines derived therefrom express trk proteins. Thus, we hypothesize that MBs arise from the failure of neuroectodermal progenitors to respond to endogenous neurotrophins. Instead of undergoing normal cell death or completing a normal program of neuronal differentiation, these progenitors may persist in the immature postnatal brain and sustain genetic mutations that result in MBs and related PNETs. Accordingly, this Project will investigate these issues by identifying the neurotrophin receptor/neurotrophin signaling pathways that may be involved in the emergence and progression of human MBs and related PNETs of the CNS.
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