Developmental loss of NT‐3 in vivo results in reduced levels of myelin‐specific proteins, a reduced extent of myelination and increased apoptosis of Schwann cells

Abstract

This work investigates the role of NT-3 in peripheral myelination. Recent articles, based in vitro, propose that NT-3 acting through its high-affinity receptor TrkC may act to inhibit myelin formation by enhancing Schwann cell motility and/or migration. Here, we investigate this hypothesis in vivo by examining myelination formation in NT-3 mutant mice. On the day of birth, soon after the onset of myelination, axons showed normal ensheathment by Schwann cells, no change in the proportion of axons which had begun to myelinate, and no change in either myelin thickness or number of myelin lamellae. However in postnatal day 21 mice, when myelination is substantially complete, we observed an unexpected reduction in mRNA and protein levels for MAG and P(0), and in myelin thickness. This is the opposite result to that predicted from previous in vitro studies, where removal of an inhibitory NT-3 signal would have been expected to enhance myelination. These results suggest that, in vivo, the importance of NT-3 as a major support factor for Schwann cells (Meier et al., (1999) J Neurosci 19:3847-3859) over-rides its potential role as an myelin inhibitor, with the net effect that loss of NT-3 results in degradation of Schwann cell functions, including myelination. In support of this idea, Schwann cells of NT-3 null mutants showed increased expression of activated caspase-3. Finally, we observed significant reduction in width of the Schwann cell periaxonal collar in NT-3 mutant animals suggesting that loss of NT-3 and resulting reduction in MAG levels may alter signaling at the axon-glial interface.

Peripheral Nerve Regeneration by Secretomes of Stem Cells from Human Exfoliated Deciduous Teeth

“…BDNF promotes motor neuron survival and differentiation [54,55]. NT-3 supports myelin formation by enhancing SC motility and migration [56,57]. CNTF is a neuroprotective agent that facilitates remyelination [58,59].…”

Neurotrophin treatment to promote regeneration after traumatic CNS injury

“…Latter studies found a promyelinating influence of NT3 via a proliferative response on oligodendrocyte progenitor cells (OPCs) (Xiao et al, 2009). Similarly, heterozygous knock outs of NT3 displayed a reduction in peripheral myelin mRNA and protein levels suggesting a promyelinating role for NT3 (Woolley et al, 2008). Myelination was also enhanced by transplantation of multi-neurotrophin-expressing glial-restricted precursor cells (GRPs) (Cao et al, 2005).…”

BDNF Exerts Contrasting Effects on Peripheral Myelination of NGF-Dependent and BDNF-Dependent DRG Neurons

“…NGF enhances Schwann cell myelination of NGF-dependent neurons via activation of neuronal TrkA receptors but has no effect on BDNF-dependent neurons which do not express TrkA (Chan et al, 2004). NT-3 inhibits peripheral myelination in vitro (Chan et al, 2001;Cosgaya et al, 2002), whereas analysis of NT3Ϫ/Ϫ mice suggests it exerts a promyelinating influence (Woolley et al, 2008). BDNF enhances peripheral myelination during development and remyelination after injury (Zhang et al, 2000;Chan et al, 2001;Cosgaya et al, 2002;Song et al, 2006).…”