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

p75神经营养蛋白受体（p75NTR）在神经干细胞核孔复杂结构和功能中的作用

• 批准号: 289346720
• 负责人: Professor Dr. Christian Schachtrup, Ph.D.
• 金额: --
• 依托单位: Anatomie II: Abteilung für Molekulare Embryologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/289346720?language=en
• 关键词: role; p75; neurotrophin; receptor; p75NTR

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.

星形胶质细胞是参与基本生物过程的复杂细胞，这些生物过程对正常脑功能至关重要。星形胶质细胞的一个主要特征是它们对损伤的反应。反应性星形胶质细胞通过形成抑制神经元再生的神经胶质瘢痕来区分损伤部位和健康组织。现在公认的是，星形胶质细胞有助于瘢痕形成的形态和功能不同。有趣的是，室管膜下区（SVZ）来源的成体神经干细胞（NSC）可以促进星形胶质细胞瘢痕形成。在健康的大脑中，SVZ神经干细胞不断地向嗅球回路添加新的神经元。然而，在CNS损伤或疾病后，SVZ衍生的NSC将其迁移路径重定向到脑损伤区域，并主要产生新生星形胶质细胞。促进NSC维持和NSC分化成星形胶质细胞的主要生长因子家族是TGF-β超家族。然而，控制NSC对TGF-β超家族信号传导的反应的分子机制以及SVZ衍生的新生星形胶质细胞对再生过程的贡献仍然难以捉摸。p75神经营养因子受体（p75 NTR）调节星形胶质细胞中控制其活化的核孔复合物结构和TGF-β信号传导。有趣的是，p75 NTR也在SVZ NSC中的核孔附近表达。我们建议的特点的作用，p75 NTR在神经干细胞核孔复合物的结构和功能调节神经干细胞的命运。我们将在体外和体内使用超分辨率显微镜鉴定p75 NTR在增殖和分化SVZ衍生的神经干细胞中的核周定位。为了确定p75 NTR在SVZ NSC命运中的作用，我们将p75 NTR-/-小鼠与携带诱导型Nestin-Cre-ERT 2/R26 R：YFP转基因的小鼠杂交，并分析SVZ衍生的NSC在创伤性脑损伤小鼠模型中的细胞命运。切割的p75 NTR与核孔复合物蛋白相互作用以促进星形胶质细胞中的TGF-β信号传导。我们将通过研究p75 NTR在神经干细胞中TGF-β/BMP诱导的信号通路中的作用来研究p75 NTR用于调节NSC命运的潜在机制，最后，我们将确定p75 NTR切割对体内NSC分化的影响。了解CNS疾病中调节神经元分化的细胞和分子机制对于开发促进功能再生的新治疗方法非常重要。