A Nogo-Like Signaling Perspective from Birth to Adulthood and in Old Age: Brain Expression Patterns of Ligands, Receptors and Modulators

Abstract

An appropriate strength of Nogo-like signaling is important to maintain synaptic homeostasis in the CNS. Disturbances have been associated with schizophrenia, MS and other diseases. Blocking Nogo-like signaling may improve recovery after spinal cord injury, stroke and traumatic brain injury. To understand the interacting roles of an increasing number of ligands, receptors and modulators engaged in Nogo-like signaling, the transcriptional activity of these genes in the same brain areas from birth to old age in the normal brain is needed. Thus, we have quantitatively mapped the innate expression of 11 important genes engaged in Nogo-like signaling. Using in situ hybridization, we located and measured the amount of mRNA encoding Nogo-A, OMgp, NgR1, NgR2, NgR3, Lingo-1, Troy, Olfactomedin, LgI1, ADAM22, and MAG, in 18 different brain areas at six different ages (P0, 1, 2, 4, 14, and 104 weeks). We show gene- and area-specific activities and how the genes undergo dynamic regulation during postnatal development and become stable during adulthood. Hippocampal areas underwent the largest changes over time. We only found differences between individual cortical areas in Troy and MAG. Subcortical areas presented the largest inter-regional differences; lateral and basolateral amygdala had markedly higher expression than other subcortical areas. The widespread differences and unique expression patterns of the different genes involved in Nogo-like signaling suggest that the functional complexes could look vastly different in different areas.

Exercise-induced Nogo-A influences rodent motor learning in a time-dependent manner

“…In the adult animal, mature CNS networks are much more stable, optimized towards optimal information flow and function [ 40 ]. Expression of Nogo-A is highly region-specific and significantly altered from the developing stage to adulthood, especially in areas of the CNS with high plasticity [ 41 , 42 ], with the notable inclusion of the motor cortex layer 2/3 [ 32 , 38 ]. Further evidence for a stabilizing function of the Nogo signaling cascade is provided by findings that network connectivity failed to stabilize in Nogo receptor-deficient mice, resulting in expansion of the critical period into adulthood [ 16 , 43 ].…”

Gene expression changes related to immune processes associate with cognitive endophenotypes of schizophrenia

“…Here, lower cognitive performance correlated with lower RTN4 expression levels. Previously Nogo has been shown to have roles in several developmental and adult synaptic plasticity related processes in the brain, including cell migration, axon guidance, and myelination (Schmandke et al, 2014), and functions including memory and motor learning (Smedfors et al, 2018). In relation to the latter process, Nogo has been demonstrated to be involved in autoimmune-mediated demyelination, a failure of the axons to regenerate after neurodegenerative disorders or injury (Karnezis et al, 2004).…”

“…Myelin dysfunction has been suggested to be involved in pathogenesis of schizophrenia (Hakak et al, 2001), and a previous study has shown decreased serum expression levels of Nogo in schizophrenia patients (Demirel et al, 2017). In addition to schizophrenia, disturbed Nogo-signalling has been associated with other psychiatric and neurological diseases, and activity of the related genes has been shown to change from birth to old age (Smedfors et al, 2018). Within the probes associated with the factor Verbal working memory, one was representing the PTGER4 gene (prostagladin E receptor 4) (q = 0.04).…”

The human neuronal receptor NgR1 bridges reovirus capsid proteins to initiate infection

“…ISVPs are characterized by an altered conformer of the σ1 protein and proteolytic removal of the σ3 protein, leading to the hypothesis that the virion conformer of σ1, outer-capsid protein σ3, or both engage NgR1. NgR1 is expressed in neural cells targeted by reovirus [31,[35][36][37] and interacts with a structurally diverse set of myelin inhibitory proteins to recruit multiple coreceptors, initiate signaling, and prevent neurite outgrowth [38][39][40][41]. There is limited structural information about how NgR1 coordinates binding to these diverse ligands and co-receptors to bring about its important functions.…”