Oligodendroglial Intrinsic Ring Finger Protein family members are injury specific, but not developmental, regulators of oligodendrocyte maturation

项目摘要： 包括轴突和髓鞘少突胶质细胞(OL)在内的白质束永久性损伤是一种 成人多发性硬化症(MS)的重要组成部分，以及导致新生儿脑损伤的 脑性瘫痪和认知障碍。然而，与人类发育髓鞘相关的调节因子 疾病和髓鞘再生的情况尚不清楚。在这两种情况下，受损的髓鞘都可以 由少突胶质细胞前体(OPC)再生，这些OPC被招募到病变中并在一个过程中分化 称为重新髓鞘形成。但这种髓鞘再生反应经常失败[1，2]，并对 持续的神经功能障碍、轴突丢失和疾病进展，了解 人类内源性损伤修复失败的机制。人们已经了解了很多关于 少突胶质细胞在再髓鞘形成中的生物学调节来自发育的研究，实际上 髓鞘再生的重述假说提出了髓鞘再生的机制 损伤本质上是发育中髓鞘形成程序的重演[3]。然而，人类的髓鞘修复是 尽管发育中的髓鞘形成具有健壮性，但极易失败，这表明 这两个过程的调控。关于是否存在少突胶质细胞的内在机制，人们知之甚少 具体作用于损伤环境而不是发展过程中的因素，以及这些因素如何发挥作用 变得不受监管。在这里，我们将少突胶质固有环指蛋白家族成员识别为损伤 少突胶质细胞成熟动力学的特定调节因子，在发育过程中不起作用，但对 重新髓鞘形成，揭示了OL固有的发育程序之间的关键调控差异 髓鞘形成和再生。在这笔赠款中，我们将1)确定无名指家庭成员的功能 RNF43(环指蛋白43)和ZNRF3(锌和环指3)在OL谱系发育和损伤中的作用 表明它们仅在损伤的情况下起调节OPC成熟动力学的作用，2)确定它们是如何 在OL谱系中被调控，并证明RNF43是识别激活的OPC响应的标记 针对人类多发性硬化症病变的损伤，3)确定其通过调节表面来抑制Wnt信号的功能 OPC上特定Frizzled型受体家族成员的呈递，以及小分子对A 卷曲的信号轴可用于促进髓鞘再生。

PROJECT ABSTRACT: Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes (OL), is an important component of Multiple Sclerosis (MS) in adults, as well as brain injuries of the newborn that cause cerebral palsy and cognitive disabilities. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. In both conditions, damaged myelin sheaths can be regenerated by oligodendrocyte precursors (OPCs) that are recruited to lesions and differentiate in a process called remyelination. But this myelin regenerative response often fails [1, 2], and contributes significantly to ongoing neurological dysfunction, axonal loss and disease progression, and it is critical to understand mechanisms underlying this failure of endogenous injury repair in humans. Much has been learnt about the regulation of oligodendrocyte biology in remyelination from the study of development, and indeed the recapitulation hypothesis of myelin regeneration proposes that mechanisms that underlie remyelination after injury are essentially a rerunning of a developmental myelination program [3]. However, human myelin repair is highly susceptible to failure, despite the robustness of developmental myelination, suggesting key differences in the regulation of the two processes. Little is understood about whether there are oligodendroglial intrinsic factors that operate specifically in the setting of injury but not in development, and how these might become dysregulated. Here we identify oligodendroglial intrinsic Ring Finger Protein family members as injury specific regulators of oligodendrocyte maturation kinetics, that do not function in development but are critical for remyelination, uncovering key regulatory differences between the OL intrinsic program of developmental myelination and regeneration. In this grant, we will 1) identify the functions of Ring Finger Family members RNF43 (Ring Finger Protein 43) and ZNRF3 (Zinc and Ring Finger 3) in development and injury in OL lineage, showing that they function to regulate OPC maturation kinetics only in the setting of injury, 2) identify how they are regulated in OL lineage, and demonstrate that RNF43 is a marker that identifies activated OPCs responding to injury in human MS lesions, 3) identify their function to repress Wnt signaling via regulation of surface presentation of specific Frizzled receptor family members on OPCs, and that small molecule manipulation of a Frizzled signaling axis can be used to promote myelin regeneration.