The role of p75 neurotrophin receptor (p75NTR) in nuclear pore complex structure and function in neural stem cells

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Astrocytes are sophisticated cells participating in fundamental biological processes that are essential for normal brain function. A major feature of astrocytes is their response to injury. Reactive astrocytes demarcate the injury site from healthy tissue by forming a glial scar that inhibits neuronal regeneration. It is now well recognized that astrocytes contributing to scar formation are morphologically and functionally different. Interestingly, subventricular zone (SVZ)-derived adult neural stem cells (NSCs) can contribute to astrocyte scar formation. In the healthy brain SVZ NSCs continuously add new neurons to the olfactory bulb circuit. However, after CNS injury or disease SVZ-derived NSCs redirect their migration path to brain lesion areas and mainly generate newborn astrocytes. A major growth factor family in promoting NSC maintenance and NSC differentiation into astrocytes is the TGF-beta superfamily. However, the molecular mechanisms that control NSC responses upon TGF-beta superfamily signaling and the contribution of SVZ-derived newborn astrocytes to regeneration processes remain elusive. The p75 neurotrophin receptor (p75NTR) regulates nuclear pore complex structure and TGF-beta signaling in astrocytes controlling their activation. Interestingly, p75NTR is also expressed in SVZ NSCs in the vicinity of the nuclear pore. We propose to characterize the role of p75NTR in NSC nuclear pore complex structure and function regulating NSC fate. We will identify the perinuclear localization of p75NTR in proliferating and differentiating SVZ-derived NSCs in vitro and in vivo using super resolution microscopy. To determine the role of p75NTR in SVZ NSC fate we will cross p75NTR-/- mice with mice carrying the inducible Nestin-Cre-ERT2/R26R:YFP transgenes and analyze the cell fate of SVZ-derived NSCs in a mouse model of traumatic brain injury. Cleaved p75NTR interacts with nuclear pore complex proteins to promote TGF-beta signaling in astrocytes. We will examine the underlying mechanism that p75NTR utilizes to regulate NSC fate by examining the role of p75NTR in TGF-beta/BMP-induced signaling pathways in neural stem cells and, finally, we will determine the effects of p75NTR cleavage on NSC differentiation in vivo. Understanding the cellular and molecular mechanisms regulating neuronal differentiation in CNS disease is important for the development of novel therapeutic approaches that promote functional regeneration.