12/8/2023 0 Comments Merlin project research groupUsing primary in vitro culture systems and in vivo mouse models, we will explore the newly discovered components of small GTPase activity control and their subsequent effect on neuronal plasticity within the adult brain. This study of activity-dependent regulation of synapse efficacy is an important pathway for the healthy aging brain.Ĭurrent thinking positions mainly guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) as the major determinants in neuronal Ras regulation. My lab research prioritizes Ras and Ras-like protein activity control in synaptic and structural neuroplasticity - the cellular basis for memory formation. This plasticity is reliant upon a continuous modification of neurons and their wiring, whereby neuronal networks are in a constant process of adaptation, resulting in the restructuring of synaptic connections. The adult brain responds and adapts to the multitude of stimuli that affect its functional and structural composition. We think we have identified a potential tumor-promoting microenvironment for Schwann cells.īrain Plasticity and the Regenerating Brain This is especially relevant for NF2 disease, considering that the cells also lack functional merlin, leaving them particularly vulnerable to an altered microenvironment. This led us to hypothesize that reduction of merlin influences intrinsic axon function and that this specific abnormal microenvironment will influence Schwann cell behavior, possibly provoking aberrant regenerative processes as well as contributing to tumorigenesis. Because of their relationship in the peripheral nervous system (PNS), we expect that these atrophic axons have a profound impact on Schwann cell behavior over time. Also, we showed that merlin regulates the crosstalk between axons and Schwann cells. From this, we could infer that the reduction of merlin in axons, independent of the tumor burden in NF2 patients, contributes to the polyneuropathies frequently observed in these cases. We have established that a reduction in NF2 gene dosage in axons causes damage resulting in axonal atrophy, which in turn causes neuropathic symptoms in mice. For instance, we have identified that merlin plays an important role in neuronal cell types involved in neuromorphogenesis, axon structure maintenance and communication between axons and Schwann cells. Moreover, our recent studies have found evidence to suggest the tumor microenvironment of schwannomas could be an important therapeutic target for NF2. We have reached the stage where we have identified signaling pathways responsible for tumor growth in Schwann cells which lack functional merlin. These are composed exclusively of Schwann cells and cover nerves and cause damage and disfiguration to the nerve as it becomes displaced. In NF2, sufferers develop tumors known as schwannomas. We want to understand how merlin functions as a tumor suppressor. Although mutations in this gene were found to be the genetic cause of NF2, we still lack a complete understanding of the action of merlin - clearly a significant obstacle to our goal of delivering effective treatments to NF2 patients. Merlin is encoded by the neurofibromin 2 tumor suppressor gene. The Morrison lab has extensive experience in NF2 research including dissecting NF2 signaling pathways and is part of the international clinical consortium Synodos. and utilizing novel mouse models for the study of tumor development in Neurofibromatosis type 2 disease (NF2).elucidating the role of the microenvironment, both during cell repair and cancer development.researching Schwann cell and axonal interactions.investigating the plasticity of the Schwann cell differentiation state.In her laboratory Morrison and her team are engaged in a number of projects related to the peripheral nervous system (PNS). Current thinking is that imbalances in this tightly regulated system result in age-related decline in nerve maintenance and regeneration as well as in hyper-proliferative disorders such as cancer. Injury prompts Schwann cells to dedifferentiate, thus becoming "repair cells", which can then switch back to be differentiated remyelinating cells. Regeneration requires axonal regrowth, in tandem with activation of a regenerative program by resident Schwann cells. These peripheral nerves, which must be maintained throughout adult life, are renowned for their remarkable ability to regenerate. Peripheral nerves are mainly composed of axonal processes from neurons and Schwann cells together they build an interactive and functional unit. It is accepted that the aging process significantly impairs the ability of peripheral nerves to regenerate after injury – but the molecular pathways that prevent efficient repair remain unknown. Current Projects Peripheral Nerve Regeneration and Aging
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