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

项目摘要： 对包括轴突和髓鞘形成的少突胶质细胞（OL）在内的白色物质束的永久性损伤是 成人多发性硬化症（MS）的重要组成部分，以及新生儿脑损伤， 脑瘫和认知障碍。然而，与人类发育髓鞘相关的调节因子 疾病和髓磷脂再生中的作用尚不清楚。在这两种情况下，受损的髓鞘都可能 由少突胶质细胞前体（OPCs）再生，这些前体被招募到病变并在一个过程中分化 叫做髓鞘再生但这种髓鞘再生反应往往失败[1，2]，并有助于显着 持续的神经功能障碍，轴突损失和疾病进展，关键是要了解 这是人类内源性损伤修复失败的潜在机制。我们已经了解了很多关于 从发育的研究中，少突胶质细胞生物学在髓鞘再生中的调节， 髓鞘再生的重演假说提出， 损伤本质上是髓鞘形成发育程序的重演[3]。然而，人类髓鞘修复是 尽管发育髓鞘形成的鲁棒性，但高度容易失败，这表明 这两个过程的调节。少突胶质细胞是否有内在的 这些因素在受伤的情况下特别起作用，但在发展中不起作用，以及这些因素如何可能 变得失调。在这里，我们确定少突胶质细胞内在环指蛋白家族成员作为损伤 少突胶质细胞成熟动力学的特异性调节因子，在发育中不起作用，但对 髓鞘再生，揭示了OL内在程序之间的关键调节差异， 髓鞘形成和再生。在这项资助中，我们将1）确定无名指家族成员的功能 RNF43（环指蛋白43）和ZNRF3（锌和环指3）在OL谱系的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）鉴定它们如何 在OL谱系中受到调控，并证明RNF43是识别激活的OPCs应答的标志物。 3）鉴定它们通过调节表面活性剂来抑制Wnt信号传导的功能， 特定卷曲受体家族成员在OPCs上的呈递，以及小分子操纵 卷曲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.