“Process” or axon outgrowth is a phenomenon well studied in neuronal cells, and is a process that requires, for the most part, a specialized structure at the tip of growing axons known as the neuronal growth cone. During development, the neuronal growth cone senses and responds to a variety of guidance cues that are expressed in the developing nervous system, and functions to guide the formation of axonal connections. An interesting feature of the neuronal growth cone is that it consists of an F-actin rich leading edge that is reminiscent of the migrating cell, and that its motility appears to be regulated by a similar array of signaling molecules that regulate the actin cytoskeleton. Examples include the classical Rho GTPases, src family kinase, as well a number of downstream actin binding proteins including the Wiscott-Aldrich syndrome protein (N-WASP) .
Interestingly, a similar growth cone structure seems to mediate process outgrowth in premyelinating oligodendrocyte precursor cells (OPCs), a key step required for oligodendrocyte maturation and axon myelination. A recent study by Rajasekharan et al. (2009) in the February 2009 issue of Development showed for the first time that OPC growth cones could respond to guidance cues that regulate neuronal growth cone motility . Specifically, this study demonstrated that the guidance cue netrin-1 could stimulate OPC growth cone motility in a manner that is similar to the neuronal growth cone. It also appeared that OPC growth cones responded to netrin-1 via conserved signaling components in the neuronal growth cone, including Rho GTPases, Fyn as well as N-WASP. Furthermore, addition of netrin-1 markedly increased OPC process outgrowth, and concomitant morphological maturation, while netrin-1 deletion significantly reduced the propensity of OPC process outgrowth. This study strongly suggested that manipulations of OPC growth cone signaling could regulate the extent of OPC process outgrowth and maturation. Given the similarities between OPC growth cones and neuronal growth cones, it is likely that compounds stimulating axon outgrowth are likely to stimulate OPC process outgrowth as well.
Can DKP101516 Promote OPC Process Outgrowth?
My thesis had been focused on identifying novel natural compounds that can stimulate growth cone motility, and to evaluate whether they could stimulate functional axonal reconnections in the central nervous system following injury. One of my key findings is the identification of a marine sponge derived compound DKP101516 that demonstrated robust axon outgrowth promoting activity [3,4]. A key question that arises is whether DKP101516 could stimulate OPC process outgrowth and morphological maturation. To address that question, I have tested the effects of DKP101516 on OPC cultures (based on a differentiation protocol I just mastered). My preliminary study suggested that DKP101516 could enhance the propensity of OPC process outgrowth. This result seems to suggest that OPC growth cone manipulations using novel natural compounds can indeed stimulate OPC process outgrowth and maturation. Perhaps this finding could be the basis for development of novel drugs that can promote myelin repair in the central nervous system.
References: (1) Li et al., 2004. Nat Neurosci.7(11):1213-21. (2) Rajasekharan et al., 2009.Development. 2009 Feb;136(3):415-26. (3) Wong et al., 2008. J Neurosci. Methods. 169, 34-42. (4) Wong et al., 2008. Exp Neurol. 214, 331-40.