Oligodendrocyte differentiation and myelination defects in OMgp null mice
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.
References (33)
- et al.
Assessment of functional recovery and axonal sprouting in oligodendrocyte-myelin glycoprotein (OMgp) null mice after spinal cord injury
Mol. Cell. Neurosci.
(2008) - et al.
The oligodendrocyte-myelin glycoprotein of mouse: primary structure and gene structure
Genomics
(1993) Regulation of oligodendrocyte development in the vertebrate CNS
Prog. Neurobiol.
(2002)- et al.
Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin
Neuron
(1994) - et al.
Oligodendrocyte myelin glycoprotein (OMgp): evolution, structure and function
Brain Res. Brain Res. Rev.
(2004) - et al.
Protein-tyrosine phosphatase alpha acts as an upstream regulator of Fyn signaling to promote oligodendrocyte differentiation and myelination
J. Biol. Chem.
(2009) - et al.
PirB is a functional receptor for myelin inhibitors of axonal regeneration
Science
(2008) - et al.
Expression of the APC tumor suppressor protein in oligodendroglia
Glia
(1996) - et al.
Age-related axonal and myelin changes in the rumpshaker mutation of the Plp gene
Acta Neuropathol. (Berl.)
(2004) - et al.
Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system
J. Neurochem.
(1998)
Glial membranes at the node of Ranvier prevent neurite outgrowth
Science
Oligodendrocyte-myelin glycoprotein (OMgp) is an inhibitor of neurite outgrowth
J. Neurochem.
Signaling from integrins to Fyn to Rho family GTPases regulates morphologic differentiation of oligodendrocytes
J. Neurosci.
LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex
Nat. Neurosci.
LINGO-1 negatively regulates myelination by oligodendrocytes
Nat. Neurosci.
LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis
Nat. Med.
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2017, Neuroscience LettersCitation Excerpt :OMgp is localized in the periaxonal processes of oligodendrocytes in the CNS with a more prominent concentration near the nodes of Ranvier where it reportedly blocks axon collateral sprouting from non-myelinated segments [70]. Consistent with this localization, OMgp null mice display defects of the nodal and perinodal architecture and hypomyelination of the spinal cord [71]. Although the subcellular localization of OMgp has been debated, it is clear that OMgp inhibits neurite outgrowth in vitro [54].
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2013, Neurobiology of DiseaseCitation Excerpt :Nogo-A appears to play a role in oligodendrocyte differentiation (Pernet et al., 2008) and the regulation of myelin internode formation (Chong et al., 2012), whereas MAG seems to play an important role in myelin formation and stabilization of axon–glial contacts (Marcus et al., 2002; Pernet et al., 2008). OMgp has recently been implicated in oligodendrocyte maturation and myelination (Lee et al., 2011). LINGO-1, one of the components of the NgR-associated receptor complex, negatively regulates oligodendrocyte differentiation and myelination (Lee et al., 2007; Mi et al., 2005, 2009).