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Abstract
The molecular mechanisms underlying the elaboration of branched processes during the later stages of oligodendrocyte maturation are not well understood. Here we describe a novel role for the chemotropic guidance cue netrin 1 and its receptor deleted in colorectal carcinoma (Dcc) in the remodeling of oligodendrocyte processes. Postmigratory, premyelinating oligodendrocytes express Dcc but not netrin 1, whereas mature myelinating oligodendrocytes express both. We demonstrate that netrin 1 promotes process extension by premyelinating oligodendrocytes in vitro and in vivo. Addition of netrin 1 to mature oligodendrocytes in vitro evoked a Dcc-dependent increase in process branching. Furthermore, expression of netrin 1 and Dcc by mature oligodendrocytes was required for the elaboration of myelin-like membrane sheets. Maturation of oligodendrocyte processes requires intracellular signaling mechanisms involving Fyn, focal adhesion kinase (FAK), neuronal Wiscott-Aldrich syndrome protein (N-WASP) and RhoA; however, the extracellular cues upstream of these proteins in oligodendrocytes are poorly defined. We identify a requirement for Src family kinase activity downstream of netrin-1-dependent process extension and branching. Using oligodendrocytes derived from Fyn knockout mice, we demonstrate that Fyn is essential for netrin-1-induced increases in process branching. Netrin 1 binding to Dcc on mature oligodendrocytes recruits Fyn to a complex with the Dcc intracellular domain that includes FAK and N-WASP, resulting in the inhibition of RhoA and inducing process remodeling. These findings support a novel role for netrin 1 in promoting oligodendrocyte process branching and myelin-like membrane sheet formation. These essential steps in oligodendroglial maturation facilitate the detection of target axons, a key step towards myelination.
Highlights
To form a myelin sheath, an oligodendrocyte initially extends multiple branching processes that survey the local environment for suitable axons (Hardy and Friedrich, 1996; Kirby et al, 2006)
Addressing the signaling mechanisms involved, we show that the Src family kinase (SFK) Fyn is required for netrin-1-induced process branching, that netrin 1 recruits Fyn to deleted in colorectal carcinoma (Dcc) in oligodendrocytes, increases SFK activity, and promotes process extension and branching associated with a decrease in RhoA activity
At P8, before myelination begins in the corticospinal tract, netrin 1 was not expressed by premyelinating oligodendrocytes (Fig. 1A-C)
Summary
To form a myelin sheath, an oligodendrocyte initially extends multiple branching processes that survey the local environment for suitable axons (Hardy and Friedrich, 1996; Kirby et al, 2006). Upon contact with a target axon, oligodendrocyte processes coalesce to form a spreading sheet of membrane that begins to wrap the axon. Laminin 2, which promotes oligodendrocyte maturation by signaling through α6β1 integrins (Baron et al, 2005), has been suggested to regulate process elaboration. Laminin-2-deficient mice have dysmyelinated and hypomyelinated axons (Chun et al, 2003). Laminin 2 is not ubiquitous in myelinated CNS axon tracts (Colognato et al, 2002) and transgenic mice lacking β1 integrin expression in oligodendrocytes exhibit no defects in CNS myelination (Benninger et al, 2006). Other ligand-receptor interactions must direct the changes in oligodendrocyte morphology required for myelination
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