Arrested Oligodendrocyte Lineage Progression During Human Cerebral White Matter Development: Dissociation Between the Timing of Progenitor Differentiation and Myelinogenesis

Abstract

Immature oligodendrocytes (OLs) derive from a large pool of late OL progenitors that populate human cerebral white matter throughout the latter half of gestation. We recently reported that a minor population of immature OLs are present in human cerebral white matter for at least 3 months before these cells commit to myelinogenesis around 30 wk postconceptional age. Since this finding supports dissociation between the events that regulate human immature OL maturation and their commitment to myelinogenesis, we characterized here the cellular sequence of events that characterize immature OLs during the transition from a premyelinating to a myelinating state. Commitment of immature OLs to myelinogenesis in human cerebral white matter correlated with the longitudinal extension of specialized processes, designated "pioneer processes," that made multiple types of apparent contacts with axons. This event coincided with the appearance of 3 distinct populations of sheaths that varied in their labeling for myelin basic protein (MBP). Since few axons initially labeled for MBP, this supported the occurrence in vivo of O4-negative, O1-positive premyelin sheaths that precede MBP-positive compacted myelin. These observations identify 3 sequential stages of early myelinogenesis: 1) the initial ensheathment of axons by premyelin sheaths generated by immature OLs; 2) the initial insertion of MBP into transitional sheaths; and 3) the generation of MBP-rich mature myelin.