Oligodendrocyte differentiation and myelination defects in OMgp null mice

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Abstract

OMgp is selectively expressed in CNS by oligodendrocyte. However, its potential role(s) in oligodendrocyte development and myelination remain unclear. We show that OMgp null mice are hypomyelinated in their spinal cords, resulting in slower ascending and descending conduction velocities compared to wild-type mice. Consistent with the hypomyelination, in the MOG induced EAE model, OMgp null mice show a more severe EAE clinical disease and slower nerve conduction velocity compared to WT animals. The contribution of OMgp to oligodendrocyte differentiation and myelination was verified using cultured oligodendrocytes from null mice. Oligodendrocytes isolated from OMgp null mice show a significant decrease in the number of MBP+ cells and in myelination compared to wild-type mice. The dramatic effects of the OMgp KO in oligodendrocyte maturation in vivo and in vitro reveal a new and important function for OMgp in regulating CNS myelination.

Introduction

Myelin provides a discontinuous insulation along axons that result in a reduction in the threshold of activation and an increase in the nerve conduction velocity (Miller and Mi, 2007). In the central nervous system, myelin is generated by oligodendrocytes. The development of oligodendrocyte lineage cells can be divided into three general stages. Oligodendrocyte progenitor cells (A2B5+ OPCs) originate from the subventricular zone at E16 to E17 (Mi et al., 2005, Miller, 2002, Miller et al., 2004, Miller and Mi, 2007). Progenitor cells subsequently proliferate, migrate throughout the CNS and differentiate into O4+ pre-myelinating oligodendrocytes (Mi et al., 2005, Miller, 2002, Miller et al., 2004, Miller and Mi, 2007). Mature oligodendrocytes express myelin basic protein (MBP) and other myelin proteins such as myelin associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP) as they differentiate. Myelination in the CNS is coordinated by the interactions of oligodendrocytes with their target axons. A detailed understanding of the mechanisms of oligodendrocyte development, myelination, and agents that facilitate oligodendrocyte differentiation is central to developing therapies for demyelinating diseases of the CNS.

Oligodendrocyte-myelin glycoprotein (OMgp) was first identified in samples prepared from the white matter of human brain (Mikol and Stefansson, 1988, Mikol et al., 1988). It contains a leucine rich repeat (LRR) domain and a glycosylphosphatidylinositol (GPI) anchor (Vourc'h and Andres, 2004). The expression of OMgp is developmentally regulated. It is expressed at low levels during embryonic stages and at high levels through adulthood (Habib et al., 1998). OMgp is expressed by oligodendrocytes in the CNS and is a component of myelin (Habib et al., 1998, Mikol and Stefansson, 1988, Mikol et al., 1988). OMgp is a ligand of Nogo receptor and PirB (Atwal et al., 2008, Wang et al., 2002). Its known function is to inhibit CNS axonal regeneration through the NgR1/LINGO-1/p75 (Troy) signaling complex (Kottis et al., 2002, Mi et al., 2004, Wang et al., 2002). We subsequently demonstrated that OMgp null mice show enhanced axon regeneration and functional recovery following spinal cord injury, as determined using the BBB scoring system (Ji et al., 2008).

OMgp protein is distributed in the axonal–glial membrane and is enriched at the nodes of Ranvier. OMgp null mice demonstrate an abnormal elongated nodal structure (Huang et al., 2005, Nie et al., 2006). Since its identification as a component of myelin in 1998, little progress has been made in understanding the function of OMgp in oligodendrocytes. The primary goal of this study was to utilize OMgp null mice to understand OMgp function in oligodendrocytes. Our studies demonstrate that OMgp plays an essential role in oligodendrocyte maturation and myelination.

Section snippets

OMgp is CNS specific

The expression of OMgp in human tissues was evaluated by Northern blot analysis (Fig. 1A and B). OMgp was highly expressed in brain, but was not detectable in non-neural tissues (Fig. 1A). OMgp expression was seen in all regions of the human brain examined (Fig. 1B) as well as in rat brain (data not shown). OMgp expression was regionally specific with high levels in the cortex and lower levels in cerebellum and spinal cord. The expression of OMpg was temporally regulated. Semi-quantitative

Discussion

Oligodendrocyte-myelin glycoprotein (OMgp) is a CNS specific, GPI-linked, leucine rich repeat protein (Habib et al., 1998, Mikol and Stefansson, 1988, Mikol et al., 1988) that is a component of myelin expressed by oligodendrocytes. Although OMgp is expressed by oligodendrocytes, its potential role(s) in regulating oligodendrocyte development or function remain unclear. The analyses of OMgp null animals have allowed for the characterization of the effects of OMgp on oligodendrocyte development

OMgp null mice

As described by Ji et al. (2008) in brief, to create an OMgp targeting construct, mouse genomic 129/Sv DNA was isolated from a lambda genomic library. The final construct deleted the entire 1–1299 nt single exon of coding sequence of OMgp (Mikol et al., 1993) and was used to target the OMgp locus in V6.5 embryonic stem (ES) cells and injected into C57BL6 blastocysts to generate chimeric mice. The chimeras were then backcrossed to C57BL6 strain mice resulting in a mixed background of 129/C57BL6.

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