Nogo‐receptor gene activity: Cellular localization and developmental regulation of mRNA in mice and humans

Abstract

Nogo (reticulon-4) is a myelin-associated protein that is expressed in three different splice variants, Nogo-A, Nogo-B, and Nogo-C. Nogo-A inhibits neurite regeneration in the central nervous system. Messenger RNA encoding Nogo is expressed in oligodendrocytes and central and peripheral neurons, but not in astrocytes or Schwann cells. Nogo is a transmembraneous protein; the extracellular domain is termed Nogo-66, and a Nogo-66-receptor (Nogo-R) has been identified. We performed in situ hybridization in human and mouse nervous tissues to map the cellular distribution of Nogo-R gene activity patterns in fetal and adult human spinal cord and sensory ganglia, adult human brain, and the nervous systems of developing and adult mice. In the human fetus Nogo-R was transcribed in the ventral horn of the spinal cord and in dorsal root ganglia. In adult human tissues Nogo-R gene activity was found in neocortex, hippocampus, amygdala, and a subset of large and medium-sized neurons of the dorsal root ganglia. Nogo-R mRNA was not expressed in the adult human spinal cord at detectable levels. In the fetal mouse, Nogo-R was diffusely expressed in brain, brainstem, trigeminal ganglion, spinal cord, and dorsal root ganglia at all stages. In the adult mouse strong Nogo-R mRNA expression was found in neurons in neocortex, hippocampus, amygdala, habenula, thalamic nuclei, brainstem, the granular cell layer of cerebellum, and the mitral cell layer of the olfactory bulb. Neurons in the adult mouse striatum, the medial septal nucleus, and spinal cord did not express Nogo-R mRNA at detectable levels. In summary, Nogo-66-R mRNA expression in humans and mice was observed in neurons of the developing nervous system Expression was downregulated in the adult spinal cord of both species, and specific expression patterns were seen in the adult brain.

Topographically specific regeneration of sensory axons in the spinal cord

“…The absence of new CGRP expression implies that sNgR does not promote significant regeneration of unmyelinated axons, as has been reported previously (8). Because unmyelinated axons lack NgR expression, they might be less responsive to a blockade of myelin-associated inhibition than myelinated axons (11). In contrast, CGRP expression recovers following ART treatment, consistent with expression of the specific ART receptor, GFRα3, on unmyelinated neurons (9,12,13), suggesting that these afferents are regenerating (Fig.…”

Nogo and Nogo‐66 receptor in human and chick: Implications for development and regeneration

“…7G). This pattern of NgR protein expression parallels the distribution of NgR RNA at 63 days of gestation (9 weeks) recently reported (Josephson et al, 2002). Little staining was observed in the white matter, with the exception of the dorsal root entry zone, where projections from the dorsal root ganglia were clearly positive (Fig.…”

“…In the system discussed here, however, it is Nogo not NgR that is present on the axons, whereas the receptor in vivo is mainly localized to neuronal cell bodies and muscle. Furthermore, in human spinal cord, as in the chick, expression of NgR protein (this study) and transcript declines with development and is virtually absent in the human adult cord (Josephson et al, 2002). Therefore, other possible roles for this signaling system, particularly during development, should be given careful consideration.…”

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

“…2). Ngr is expressed, albeit at different levels, on the surface of various neurons 33 . It is an 85 kDa GPI-linked protein that contains a series of LRRs clustered in two groups -a series of eight, and a second series closer to the membrane-associated GPI-linked terminus of the protein (LRRCT, leucine rich repeats C-terminal).…”