Development of a complex process network by maturing oligodendrocytes is a critical but currently poorly characterized step toward myelination. Here, we demonstrate that the matricellular oligodendrocyte-derived protein phosphodiesterase-Iα/autotaxin (PD-Iα/ATX) and especially its MORFO domain are able to promote this developmental step. In particular, the single EF hand-like motif located within PD-Iα/ATX's MORFO domain was found to stimulate the outgrowth of higher order branches but not process elongation. This motif was also observed to be critical for the stimulatory effect of PD-Iα/ATX's MORFO domain on the reorganization of focal adhesions located at the leading edge of oligodendroglial protrusions. Collectively, our data suggest that PD-Iα/ATX promotes oligodendroglial process network formation and expansion via the cooperative action of multiple functional sites located within the MORFO domain and more specifically, a novel signaling pathway mediated by the single EF hand-like motif and regulating the correlated events of process outgrowth and focal adhesion organization.

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During development, postmigratory, premyelinating oligodendrocytes extend processes that navigate through the central nervous system (CNS) environment, where they recognize a number of extracellular cues, including axonal segments to be myelinated. Ultimately this recognition event leads to the formation of the CNS myelin sheath. However, the morphological structures and molecular mechanisms that control such oligodendroglial pathfinding are poorly understood. Here we show that postmigratory, premyelinating oligodendrocyte processes possess at their distal tips expansions that ultrastructurally resemble growth cones of postmigratory neurons and that we will refer to as OLG-growth cones. OLG-growth cones are highly motile and capable of mediating process outgrowth, retraction, and branching. In addition, they express regulators of cytoskeletal organization, GAP43 and cofilin, that are known to mediate neuronal growth cone navigation. In a choice situation, processes of postmigratory, premyelinating oligodendrocytes and their OLG-growth cones have the ability to selectively avoid a nonpermissive substrate, that is, collagen IV. Thus, our findings provide, for the first time, a detailed characterization of sensorimotor structures present at the tips of postmigratory, premyelinating oligodendrocyte processes. Furthermore, the data presented here suggest that, although the cellular mechanisms involved in growth cone steering may be similar for postmigratory neuronal and oligodendroglial cells, extracellular cues may be interpreted in a cell-type-specific fashion.

Our previous results support the idea that CREB (cyclic AMP-response element binding protein) may be a mediator of neuroligand and growth factor signals that, coupled to different signal transduction pathways, play different roles at specific stages of oligodendrocyte development. In the early stages, when cells are immature precursors, CREB may play a role as a mediator of protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) pathways regulating cell proliferation. In contrast, at a later stage, when cells are already committed oligodendrocytes, CREB seems to play an important role as a mediator in the stimulation of myelin basic protein (MBP) expression by cyclic AMP (cAMP). In this study, we have investigated whether cAMP and CREB play a role in regulating the expression of all or on the other hand particular MBP isoforms. The results indicated that treatment of committed oligodendrocytes with the cAMP analogue db-cAMP results in a pattern of expression of MBP-related polypeptides that most closely resembles the pattern of MBPs observed in cerebra from adult animals. Experiments in which CREB expression was inhibited using a CREB antisense oligonucleotide, suggested that CREB is involved in the cAMP-dependent stimulation of all the MBP isoforms. In contrast, we have found that db-cAMP stimulates the expression of myelin proteolipid protein (PLP) in a process that occurs despite inhibition of CREB expression. These results support the idea that cAMP stimulates the maturation of oligodendrocytes and stress the fact multiple mechanisms may convey the action of this second messenger modulating oligodendrocyte differentiation and myelination.

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