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.

PROJECT NARRATIVE: Myelin regeneration often fails in Multiple Sclerosis and contributes significantly to ongoing neurological dysfunction, axonal loss and disease progression. Here we identify oligodendroglial intrinsic Ring Finger Protein family members as injury specific regulators of oligodendrocyte maturation, that do not function in development but are critical for remyelination, uncovering key regulatory differences between the Oligodendrocyte intrinsic program of developmental myelination and regeneration. This grant will help us to better understand the regulation of human remyelination, and identify targets for therapeutic intervention in this debilitating condition.