Involvement of the Myelin-Associated Inhibitor Nogo-A in Early Cortical Development and Neuronal Maturation

Abstract

Nogo-A is a myelin-associated protein expressed by neurons and myelinating mature oligodendrocytes in the central nervous system. Although most research has focused on the participation of Nogo-A in the prevention of axonal regeneration and plasticity in the adult, little attention has been paid to the putative functions of Nogo-A during embryonic development. Here we examined the general pattern and cell-specific distribution of Nogo-A in the prenatal mouse telencephalon. In addition, we studied the development of the major axon tracts and radial and tangential migration in Nogo-A/B/C knockout mice. The pattern of Nogo-A showed distinct distribution in radial glia and postmitotic neurons, in which it is particularly enriched in developing axons. Similarly, Nogo-A was enriched at the leading process of tangentially migrating interneurons but not detectable in radial migrating neurons. Although a low level of Nogo-A appears to be on the surface of many cortical neurons, most proteins have intracellular localization. In Nogo-deficient background, neurons displayed early polarization and increased branching in vitro, probably reflecting a cell-intrinsic role of Nogo proteins in branching reduction, and early tangential migration was delayed. On the basis of these observations, we propose that Nogo proteins, particularly Nogo-A, are involved in multiple processes during cortical development.

Amino-Nogo-A antagonizes reactive oxygen species generation and protects immature primary cortical neurons from oxidative toxicity

“…These data are consistent with previous studies. 7,8 We then determined the membrane topology of aminoNogo-A in cortical neurons using living cell staining with A620, 1E8 and A201 antibodies. 15 The data indicate that amino-Nogo-A is present intracellularly in developing cortical neurons ( Figure 1c).…”

“…[6][7][8] However, its pathophysiological role has remained unclear. Here, we showed for the first time evidence establishing a novel cell-autonomous neuroprotective role of amino-Nogo-A against oxidative stress (e.g., H 2 O 2 ) and identifying a mechanism of amino-Nogo-A-mediated signaltransduction pathway of scavenging ROS (Figure 8l).…”

“…4,5 Besides mature oligodendrocytes, several subtypes of neurons express Nogo-A proteins, particularly in the developing nervous system. [6][7][8] Unlike the well-known functions and signal pathways of oligodendrocyte-derived Nogo-A, 1,2 the important features of neuronal Nogo-A are beginning to be understood. In the developing forebrain cortex, Nogo-A is expressed in radial glia cells, postmitotic neuronal precursors and cortical neurons.…”

“…In mice lacking Nogo-A, radial and tangential migrations of neural precursors and interneurons are influenced in early cortical development and neuronal maturation. 8 Cultured dorsal root ganglia (DRG) neurons from Nogo-A KO mice or Nogo-A antibodies neutralization experiments suggest that neuronal Nogo-A regulates neurite fasciculation, branching and extension. 9 In the adult CNS, Nogo-A proteins are located at synapse and restrict synaptic plasticity 10 and stabilize the architecture of hippocampal neurons.…”

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

“…12 Nogo-A and NgR1 were shown to regulate synaptic plasticity, for example, long-term potentiation in the hippocampus and in the sensory-motor cortex, [18][19][20][21][22] whereas the effects of neuronal Nogo-A after injury are not yet well understood. During development, neuronal Nogo-A influences neuronal migration, 23,24 survival, 25,26 cell spreading and neurite growth. 27,28 In injured adult retinal ganglion cells (RGCs), silencing neuronal Nogo-A resulted in a marked reduction of regenerative sprouting and decreased expression of growth-associated molecules.…”