Functional development of oligodendrocytes

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During development, both oligodendrocytes and Schwann cells pass through a number of physiologically distinct stages that can be identified by the expression of stage-specific antigens and are characterized by marked changes in proliferation, migration, morphology and function. Oligodendrocyte progenitor cells (OPCs) develop in highly localized ventricular zones in the brain and spinal cord, by a process that depends on the transcription factors Oligl, Olig2, SOXIO and Nkx2.2, and the signalling molecules sonic hedgehog (Shh), bone morphogenic protein (BMP), and Notch. These transcription factors regulate key stages of OPC development and oligodendrocyte specification; Olig2 and Nkx2.2 are expressed by NG2-glia and have a continued role in the generation of oligodendrocytes throughout life. OPC migrate to their final sites in the brain and spinal cord, where they undergo local proliferation and differentiation, or apoptosis, in response to diffusible growth factors, interactions with the extracellular matrix, and diffusible and membrane-bound signals from axons and glia. OPCs can be identified by their expression of platelet-derived growth factor alpha receptors (PDGFaR), the GD3 ganglioside, and the NG2 CSPG. As OPCs differentiate they gain expression of the sulphatides recognized by the O4 antibody and develop into cells variously called pro-oligodendrocytes, pre-oligodendrocytes, or promyelinating oligodendrocytes. These 'promyelinating' oligodendrocytes lose PDGFaR, GD3 and NG2 as they gain expression of GalC, without losing O4. As these cells form contacts with their target axons they exit the cell cycle and develop into premyelinating oligo-dendrocytes, which begin to express myelin-related gene products, prior to axon ensheathment and myelination. CNP is one of the earliest oligodendrocyte-specific proteins expressed, and the two isoforms are temporally regulated, with CNP2 being expressed by OPCs, and both CNP1 and CNP2 being expressed at the time of oligodendrocyte differentiation. This is followed by expression of MBP, PLP and

MAG, prior to myelination. The antibody Rip is a useful tool for studying terminal oligodendrocyte differentiation and myelination, but its epitope is unknown. The expression of PLP/DM20 is of interest, because DM20 dominates during the early stages of development and the mRNA can be expressed by OPCs. During differentiation, DM20 declines and PLP is the dominant form during myelination and later. MOBPs are expressed in the late stages of myelination, significantly later than expression of MBP. MOG is one of the last myelin proteins to be expressed and is often used as a marker for mature oligodendrocytes.

The various markers determine oligodendrocyte functions at different stages of differentiation. PDGFaR mediates the effects of PDGF-AA, which is a potent mitogen and survival factor for OPCs and stimulates migration. The loss of PDGFaR signifies a decrease in the migratory and proliferative capacity of OPCs, and a switch to the dependence on axon-derived factors for survival and differentiation. The precise functions of GD3 and NG2 in OPCs are unresolved, but their interactions with the ECM, integrins and the intracellular cytoskeleton indicate they are likely to mediate migration, process outgrowth, cell-cell recognition and adhesion. The developmental expression of galactolipids, sulphatides and myelin proteins are essential for myelination and axon development and integrity. The early expression of CNP, PLP and MAG are likely to be important in process outgrowth, axon recognition, and ensheathment (see Chapter 8.3.3).

Oligodendrocyte differentiation is regulated by a variety of growth factors. PDGF-AA is the best characterized mitogen and survival factor for OPCs. Fibrob-last growth factor 2 (FGF2) is a mitogen for OPCs and inhibits their differentiation into oligodendrocytes, at least partly by maintaining expression of PDGFaR. Expression of FGF receptors is developmentally regulated in oligodendrocytes: FGF-R1 increases as cells mature; FGF-R2 is expressed throughout the lineage; FGF-R3 is expressed transiently by premyelinating oligodendrocytes and is important in the initiation of myelination. Insulin-like growth factor I (IGF-I) is a survival factor for oligodendrocytes and with thyroid hormone promotes differentiation. The precise interactions of these trophic factors in vivo are unresolved. When OPCs reach their final destinations, contact with axons may be sufficient for survival and differentiation, under the influence of neuregulin-1 (NRG-1) and Notch/Jagged signalling.

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