MT1-MMP调控Notch信号通路影响神经干细胞自我更新及分化

Neurogenesis refers to the generation of neurons from neural stem and progenitor cells. It is important for neuronal plasticity, injury repair, environmental adaptation, learning and memory. Notch signaling is critical for neurogenesis by regulating the self-renewal and differentiation of neural stem cells (NSCs) and neural progenitor cells (NPCs). Increased Notch signaling favors the maintenance of multipotency in NSCs. The activation of Notch signaling is triggered by the binding of the ligand to the receptor followed by the stepwise proteolytic cleavages of the receptor, leading to the release of active Notch intracellular domain (NICD) which is translocated into nucleus where it forms complex with constitutive DNA binding protein CSL to activate the transcription of downstream target genes such as the HES family. Receptor cleavage by secretases is critical for the activation of Notch signaling. Notch signaling is also regulated by the sheddases of the ligands on the cell surface. MT1-MMP, a major cell surface matrix metalloproteinase required for extracellular matrix remodeling and pericellular proteolysis, was found to cleave Dll1 on bone marrow stromal cells (BMSCs) to negatively modulate Notch signaling in hematopoietic progenitors. MT1-MMP is highly expressed in wall of ventricular zone and in subventricular zone of developing brain where NSCs and niches reside. Our preliminary data showed that neurospheres derived from MT1-MMP-/- brains are significantly larger than that from wild-types. In addition, active Notch intracellular fragment is significantly increased in MT1-MMP-/- neurospheres, suggesting potential role for MT1-MMP in NSCs and NPCs. We hypothesize that MT1-MMP could modulate Notch signaling to regulated self-renewal and differentiation in NSCs/NPCs. We propose to characterize the NSCs/NPCs in MT1-MMP-/- mice in great detail both in vitro and in vivo, in terms of self-renewal capacity and differentiation, to understand how MT1-MMP contributes to neurogenesis. The proposed study will allow us to understand how MT1-MMP impacts the NSCs/NPCs and reveal the molecular mechanism underlying defective neurogenesis in MT1-MMP-/- mice. In addition, this study will provide insights into MT1-MMP-mediated regulation of Notch signaling in neurogenesis and neuroblastoma。

神经生成是指从神经干细胞（NSCs）和神经祖细胞（NPCs）生成神经元。神经生成对于神经可塑性，损伤修复，环境适应，学习和记忆至关重要。Notch信号通过调节NSCs和NPCs的自我更新和分化对神经生成起关键作用。 MT1-MMP是胞外基质重塑和细胞表面蛋白质水解所必需的膜基质金属蛋白酶，在发育中的大脑神经干细胞富集的脑室区壁和脑室下区高表达。MT1-MMP可剪切骨髓干细胞上的DLL1从而下调Notch信号。MT1-MMP-/-神经球明显大于野生型，NICD1也显着增加，提示MT1-MMP对NSCs/NPCs具有重要作用。本研究旨在深入探讨MT1-MMP对NSCs/NPCs的自我更新和分化的影响，阐述MT1-MMP如何影响神经生成，揭示MT1-MMP缺失小鼠神经生成异常的分子机制，为Notch信号介导的神经系统恶性肿瘤的发生发展及应对措施提供理论依据。

神经系统中，神经干细胞具有分化为神经元、星形胶质细胞和少突胶质细胞的潜能，从而能够产生大量脑细胞组织。MT1-MMP 是胞外基质重塑和细胞表面蛋白质水解所必需的膜基质金属蛋白酶，在发育中大脑神经干细胞富集的脑室区壁和脑室下区高表达，并表达于神经干细胞及神经胶质细胞。Notch 信号通过调节NSCs 和 NPCs 的自我更新和分化对神经生成起关键作用。之前的研究已证实MT1-MMP 可剪切骨髓干细胞上的DLL1 从而下调 Notch 信号以维持正常淋巴细胞发育。MT1-MMP-/-神经球明显大于野生型，NICD1 的表达也显著增加，提示 MT1-MMP 对NSCs/NPCs 具有重要作用。 本研究旨在深入探讨 MT1-MMP 对 NSCs/NPCs 的自我更新和分化的影响，并阐述 MT1-MMP 是否影响神经细胞的生成及分化，以及揭示 MT1-MMP 缺失小鼠神经生成异常的分子机制，为 Notch 信号介导的神经系统恶性肿瘤的发生发展及应对措施提供理论依据。