PTPα Acts As A Negative Modulator Of Myelination Of Small CNS Axons

Myelination is a complex progress required for the rapid saltatory conduction of action potential of nerve fibers. Myelination is coordinated by the axon-glia interaction though the mechanism of the myelination which remains little known. Receptor protein tyrosine phosphatase (RPTP) family, such as PTPε, PTPδ and LAR, is involved in neural development and myelination. In the absence of these molecules, the thickness of myelin decreases (Elchebly et al., 1999; Peretz et al., 2000; Xie et al., 2001). Phosphacan, the secreted form of RPTPβ (Maurel et al., 1994), localizes at node of Ranvier. RPTPβ associates with sodium channels (Ratcliffe et al., 2000) and modulates with sodium channel currents. PTPα can activate fyn, a molecule suggested to play a great role in myelination (Bhandari et al., 1998; Harder, et al., 1998; Ponniah et al., 1999). In addition, PTPα associates with F3/contactin which is also involved in the same complex with fyn. F3/contactin, a paranodal molecules, can promote maturation and differentiation of oligodendrocyes by Notch/Deltex1 pathway. These facts suggest that PTPα possibly play some roles in myelination. We explore the role PTPα in myelination using PTPα knockout mice. In the absence of PTPα, the myelin thickness increases, especially in small axons. The unattached paranodal loops contribute to the increase since the number of attched loops remains unchanged. We have checked the alteration of myelin related proteins in PTPα knockout mice and found that the expression of myelin related proteins have no obvious change. However, the increase of proportion of small axons in absence of PTPα may explain why there is no obvious change in expression of myelin related proteins. We further found that PTPα can modulate the clustering of F3/contactin at paranode, since the transverse bands appeared earlier in the absence of PTPα. This point has been confirmed in in vitro. The clustering of F3/contactin can promote myelination by Notch/Deltex1 pathway. Thus, PTPα is a negative modulator in ensheathment via modulating F3/contactin clustering to trigger Notch/Deltex1 signaling pathway at axoglial junction during myelination.