Short‐term low‐frequency electrical stimulation enhanced remyelination of injured peripheral nerves by inducing the promyelination effect of brain‐derived neurotrophic factor on Schwann cell polarization

Electrical stimulation (ES) has been found to aid repair of nerve injuries and have been shown to increase and direct neurite outgrowth during stimulation. However, the effect of ES on peripheral remyelination after nerve damage has been investigated less well, and the mechanism underlying its action remains unclear. In the present study, the crush‐injured sciatic nerves in rats were subjected to 1 hr of continuous ES (20 Hz, 100 μsec, 3 V). Electron microscopy and nerve morphometry were performed to investigate the extent of regenerated nerve myelination. The expression profiles of P0, Par‐3, and brain‐derived neurotrophic factor (BDNF) in the injuried sciatic nerves and in the dorsal root ganglion neuron/Schwann cell cocultures were examined by Western blotting. Par‐3 localization in the sciatic nerves was determined by immunohistochemistry to demonstrate Schwann cell polarization during myelination. We reported that 20‐Hz ES increased the number of myelinated fibers and the thickness myelin sheath at 4 and 8 weeks postinjury. P0 level in the ES‐treated groups, both in vitro and in vivo, was enhanced compared with the controls. The earlier peak of Par‐3 in the ES‐treated groups indicated an earlier initiation of Schwann cell myelination. Additionally, ES significantly elevated BDNF expression in nerve tissues and in cocultures. ES on the site of nerve injury potentiates axonal regrowth and myelin maturation during peripheral nerve regeneration. Furthermore, the therapeutic actions of ES on myelination are mediated via enhanced BDNF signals, which drive the promyelination effect on Schwann cells at the onset of myelination. © 2010 Wiley‐Liss, Inc.     

Rab27a/Slp2-a complex is involved in Schwann cell myelination

Myelination of Schwann cells in the peripheral nervous system is an intricate process involving myelin protein traffcking. Recently, the role and mechanism of the endosomal/lysosomal system in myelin formation were emphasized. Our previous results demonstrated that a small GTPase Rab27a regulates lysosomal exocytosis and myelin protein traffcking in Schwann cells. In this present study, we established a dorsal root ganglion (DRG) neuron and Schwann cell co-culture model to identify the signals associated with Rab27a during myelin-ation. First, Slp2-a, as the Rab27a effector, was endogenously expressed in Schwann cells. Second, Rab27a expression signiifcantly increased during Schwann cell myelination. Finally, Rab27a and Slp2-a silencing in Schwann cells not only reduced myelin protein expression, but also impaired formation of myelin-like membranes in DRG neuron and Schwann cell co-cultures. Our ifndings suggest that the Rab27a/Slp2-a complex affects Schwann cell myelinationin vitro.     

SNX27, a protein involved in down syndrome,regulates GPR17 trafficking and oligodendrocyte differentiation

The G protein‐coupled receptor 17 (GPR17) plays crucial roles in myelination. It is highly expressed during transition of oligodendrocyte progenitor cells to immature oligodendrocytes, but, after this stage, it must be down‐regulated to allow generation of mature myelinating cells. After endocytosis, GPR17 is sorted into lysosomes for degradation or recycled to the plasma membrane. Balance between degradation and recycling is important for modulation of receptor levels at the cell surface and thus for the silencing/activation of GPR17‐signaling pathways that, in turn, affect oligodendrocyte differentiation. The molecular mechanisms at the basis of these processes are still partially unknown and their characterization will allow a better understanding of myelination and provide cues to interpret the consequences of GPR17 dysfunction in diseases. Here, we demonstrate that the endocytic trafficking of GPR17 is mediated by the interaction of a type I PDZ‐binding motif located at the C‐terminus of the receptor and SNX27, a recently identified protein of the endosome‐associated retromer complex and whose functions in oligodendrocytes have never been studied. SNX27 knock‐down significantly reduces GPR17 plasma membrane recycling in differentiating oligodendrocytes while accelerating cells' terminal maturation. Interestingly, trisomy‐linked down‐regulation of SNX27 expression in the brain of Ts65Dn mice, a model of Down syndrome, correlates with a decrease in GPR17⁺ cells and an increase in mature oligodendrocytes, which, however, fail in reaching full maturation, eventually leading to hypomyelination. Our data demonstrate that SNX27 modulates GPR17 plasma membrane recycling and stability, and that disruption of the SNX27/GPR17 interaction might contribute to pathological oligodendrocyte differentiation defects. GLIA 2016. GLIA 2016;64:1437–1460     

孕期缺铁对婴幼儿运动发育的研究进展

铁缺乏(ID)和缺铁性贫血(IDA)是全球最常见的单一营养缺乏性疾病。孕妇和婴幼儿是ID的高危人群,孕母ID到一定程度会影响胎儿/新生儿的铁营养状况。早期ID主要通过影响髓鞘化、纹状体和多巴胺神经递质影响个体的运动发育。生后早期给予足量的铁剂治疗能纠正婴幼儿循环及组织内的ID,但无法完全逆转孕期ID所致的行为改变。深入研究孕期ID对婴幼儿运动发育的影响及其可逆性,明确铁剂治疗的关键时间窗,对提高儿童生存质量,改善远期预后具有十分重要的意义。     

CNS myelination requires cytoplasmic dynein function

Background: Cytoplasmic dynein provides the main motor force for minus‐end‐directed transport of cargo on microtubules. Within the vertebrate central nervous system (CNS), proliferation, neuronal migration, and retrograde axon transport are among the cellular functions known to require dynein. Accordingly, mutations of DYNC1H1, which encodes the heavy chain subunit of cytoplasmic dynein, have been linked to developmental brain malformations and axonal pathologies. Oligodendrocytes, the myelinating glial cell type of the CNS, migrate from their origins to their target axons and subsequently extend multiple long processes that ensheath axons with specialized insulating membrane. These processes are filled with microtubules, which facilitate molecular transport of myelin components. However, whether oligodendrocytes require cytoplasmic dynein to ensheath axons with myelin is not known. Results: We identified a mutation of zebrafish dync1h1 in a forward genetic screen that caused a deficit of oligodendrocytes. Using in vivo imaging and gene expression analyses, we additionally found evidence that dync1h1 promotes axon ensheathment and myelin gene expression. Conclusions: In addition to its well known roles in axon transport and neuronal migration, cytoplasmic dynein contributes to neural development by promoting myelination. Developmental Dynamics 244:134–145, 2015. © 2014 Wiley Periodicals, Inc.     

Neuregulin-1在外周神经再生中的作用

人类外周神经再生通常导致永久性的功能丧失。在外周神经再生过程中,雪旺细胞发挥重要的作用,它可以包绕神经轴突形成髓鞘,并分泌各种神经营养因子。在这个过程中,NRG-1起着重要的作用。NRG-1通过信号传导,使雪旺细胞去分化,增殖。而且NRG-1调节神经轴突的髓鞘化,并决定髓鞘的厚度。最后,在神经肌肉接头形成的过程中,NRG-1 也起着重要的作用。总之,NRG-1促进了外周神经损伤后的再生。     

Spatiotemporal distribution and function of N‐cadherin in postnatal Schwann cells: A matter of adhesion?

During embryonic development of the peripheral nervous system (PNS), the adhesion molecule neuronal cadherin (N‐cadherin) is expressed by Schwann cell precursors and associated with axonal growth cones. N‐cadherin expression levels decrease as precursors differentiate into Schwann cells. In this study, we investigated the distribution of N‐cadherin in the developing postnatal and adult rat peripheral nervous system. N‐cadherin was found primarily in ensheathing glia throughout development, concentrated at neuron–glial or glial–glial contacts of the sciatic nerve, dorsal root ganglia (DRG), and myenteric plexi. In the sciatic nerve, N‐cadherin decreases with age and progress of myelination. In adult animals, N‐cadherin was found exclusively in nonmyelinating Schwann cells. The distribution of N‐cadherin in developing E17 DRG primary cultures is similar to what was observed in vivo. Functional studies of N‐cadherin in these cultures, using the antagonist peptide INPISGQ, show a disruption of the attachment between Schwann cells, but no interference in the initial or long‐term contact between Schwann cells and axons. We suggest that N‐cadherin acts primarily in the adhesion between glial cells during postnatal development. It may form adherents/junctions between nonmyelinating glia, which contribute to the stable tubular structure encapsulating thin caliber axons and thus stabilize the nerve structure as a whole. © 2010 Wiley‐Liss, Inc.