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.

The formation of the myelin sheath is a crucial step during development since it enables fast and efficient propagation of signals within the limited space of the mammalian central nervous system (CNS). During the process of myelination, oligodendrocytes actively interact with the extracellular matrix (ECM), and these interactions are considered crucial for proper and timely completion of the myelin sheath. However, the exact regulatory circuits involved in the signaling events that occur between the ECM and oligodendrocytes are currently not fully understood. In the present study we, therefore, investigated the role of a known integrator of cell-ECM signaling, namely focal adhesion kinase (FAK), in CNS myelination via the use of conditional (oligodendrocyte-specific) and inducible FAK knock-out mice (Fakflox/flox:PLP/CreERT mice). When inducing FAK knock-out just prior to and during active myelination of the optic nerve, we observed a significant reduction in the number of myelinated fibers at postnatal day 14. In addition, our data revealed a decreased number of primary processes extending from oligodendrocyte cell bodies at this postnatal age and upon induction of FAK knock-out. In contrast, myelination appeared normal at postnatal day 28. Thus, our data suggest that FAK controls the efficiency and timing of CNS myelination during its initial stages by, at least in part, regulating oligodendrocyte process outgrowth and/or remodeling.

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