Knockout of p75^NTR impairs re‐myelination of injured sciatic nerve in mice

Abstract

Remyelination is an important aspect of nerve regeneration after nerve injury but the underlying mechanisms are not fully understood. The neurotrophin receptor, p75NTR , in activated Schwann cells in the Wallerian degenerated nerve is up-regulated and may play a role in the remyelination of regenerating peripheral nerves. In the present study, the role of p75 NTR in remyelination of the sciatic nerve was investigated in p75 NTR mutant mice. Histological results showed that the number of myelinated axons and thickness of myelin sheath in the injured sciatic nerves were reduced in mutant mice compared with wild-type mice. The myelin sheath of axons in the intact sciatic nerve of adult mutant mice is also thinner than that of wild-type mice. Real-time RT-PCR showed that mRNA levels for myelin basic protein and P0 in the injured sciatic nerves were significantly reduced in p75 NTR mutant animals.Western blots also showed a significant reduction of P0 protein in the injured sciatic nerves of mutant animals. These results suggest that p75 NTR is important for the myelinogenesis during the regeneration of peripheral nerves after injury.

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

“…2, available at www.jneurosci.org as supplemental material). Interestingly, analysis of the p75NTRϪ/Ϫ mice has identified that p75NTR acts as a positive modulator of peripheral myelination; however, the cell type responsible is unknown (Bentley and Lee, 2000;Cosgaya et al, 2002;Song et al, 2006). To investigate whether neuronal p75NTR receptors mediate the promyelinating influence of BDNF, we used a mixed species coculture, using NGF-dependent neurons isolated from p75NTR Ϫ/Ϫ mice (Lee et al, 1992) (Fig.…”

“…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). BDNF can be transported along and secreted by DRG axons to enhance Schwann cell myelination and induce Schwann cell polarity, a necessary step in the induction of myelination (Chan et al, 2006;Ng et al, 2007).…”

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

“…To examine myelination in adulthood, we used a sciatic nerve crush model in which the damaged axons regenerate and become remyelinated (20,21). We assessed the efficiency of remyelination by an established nerve histomorphometry method (22).…”

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

“…Survival and proliferation of cortical astrocytes (Sibilia et al 1998;Wagner et al 2006); Astrocyte development and neuronal survival (Kornblum et al 1998 Regulation of neural tube development (Deng et al 1997;Hasegawa et al 2004); OL differentiation (Zhou et al 2006) p75NTR Negative regulation of hippocampal pyramidal neuron dendritic morphology and neurite outgrowth (Zagrebelsky et al 2005); Schwann cell migration, remyelination (Bentley and Lee 2000;Song et al 2006;Tomita et al 2007) TrkA Development of sensory sympathetic and cholinergic neurons Fagan et al 1996) TrkB Development of motor and/or sensory neurons (Ernfors et al 1994;Klein 1994;Pinon et al 1996); Interneuron migration (Polleux et al 2002) TrkC Development of sensory neurons Liebl et al 1997) 1998; Hirota et al 2004), in which cytoplasmic domains of the receptor are no longer accessible to signaling proteins, rendering the receptor signaling incompetent. Moreover, the increasingly acidic lysosomal environment ( pH 4.0) promotes protein degradation.…”