Mechanisms and functional implications of adult neurogenesis.

Trk receptors are a family of three receptor tyrosine kinases, each of which can be activated by one or more of four neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3 and NT4). Neurotrophin signaling through these receptors regulates cell survival, proliferation, the fate of neural precursors, axon and dendrite growth and patterning, and the expression and activity of functionally important proteins, such as ion channels and neurotransmitter receptors. In the adult nervous system, the Trk receptors regulate synaptic strength and plasticity. The cytoplasmic domains of Trk receptors contain several sites of tyrosine phosphorylation that recruit intermediates in intracellular signaling cascades. As a result, Trk receptor signaling activates several small G proteins, including Ras, Rap-1, and the Cdc-42-Rac-Rho family, as well as pathways regulated by MAP kinase, PI 3-kinase and phospholipase-C-gamma (PLC-gamma). Trk receptor activation has different consequences in different cells, and the specificity of downstream Trk receptor-mediated signaling is controlled through expression of intermediates in these signaling pathways and membrane trafficking that regulates localization of different signaling constituents. Perhaps the most fascinating aspect of Trk receptor-mediated signaling is its interplay with signaling promoted by the pan-neurotrophin receptor p75NTR. p75NTR activates a distinct set of signaling pathways within cells that are in some instances synergistic and in other instances antagonistic to those activated by Trk receptors. Several of these are proapoptotic but are suppressed by Trk receptor-initiated signaling. p75NTR also influences the conformations of Trk receptors; this modifies ligand-binding specificity and affinity with important developmental consequences.

Trk receptors: roles in neuronal signal transduction.

The neurotrophins are a family of proteins that are essential for the development of the vertebrate nervous system. Each neurotrophin can signal through two different types of cell surface receptor — the Trk receptor tyrosine kinases and the p75 neurotrophin receptor. Given the wide range of activities that are now associated with neurotrophins, it is probable that additional regulatory events and signalling systems are involved. Here, I review recent findings that neurotrophins, in addition to promoting survival and differentiation, exert various effects through surprising interactions with other receptors and ion channels.

/pdf/neurotrophins-and-their-receptors-a-convergence-point-for-3hfqpg5jyn.pdf

Neurotrophins and their receptors: a convergence point for many signalling pathways.

Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-g1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-kB (NF-kB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.

/pdf/neurotrophin-regulated-signalling-pathways-30f9o18vav.pdf

Neurotrophin-regulated signalling pathways

Substantial advances have elucidated some of the central mechanisms underlying the inflammation, demyelination, and neurodegeneration that occur in multiple sclerosis Correspondingly, the clinical strategies available for the management of the disease have widened This review focuses on the current knowledge of the pathogenesis of the inflammatory and neurodegenerative elements of the multiple sclerosis plaque

Multiple Sclerosis — The Plaque and Its Pathogenesis

The inhibitory activity associated with myelin is a major obstacle for successful axon regeneration in the adult mammalian central nervous system (CNS)1,2. In addition to myelin-associated glycoprotein (MAG)3,4 and Nogo-A5,6,7, available evidence suggests the existence of additional inhibitors in CNS myelin8. We show here that a glycosylphosphatidylinositol (GPI)-anchored CNS myelin protein, oligodendrocyte-myelin glycoprotein (OMgp), is a potent inhibitor of neurite outgrowth in cultured neurons. Like Nogo-A, OMgp contributes significantly to the inhibitory activity associated with CNS myelin. To further elucidate the mechanisms that mediate this inhibitory activity of OMgp, we screened an expression library and identified the Nogo receptor (NgR)9 as a high-affinity OMgp-binding protein. Cleavage of NgR and other GPI-linked proteins from the cell surface renders axons of dorsal root ganglia insensitive to OMgp. Introduction of exogenous NgR confers OMgp responsiveness to otherwise insensitive neurons. Thus, OMgp is an important inhibitor of neurite outgrowth that acts through NgR and its associated receptor complex. Interfering with the OMgp/NgR pathway may allow lesioned axons to regenerate after injury in vivo.

http://labs.icb.ufmg.br/lbcd/prodabi5/homepages/hugo/Hugo/nogoreceptor.pdf

Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth.

In inhibiting neurite outgrowth, several myelin components, including the extracellular domain of Nogo-A (Nogo-66)1, oligodendrocyte myelin glycoprotein (OMgp)2 and myelin-associated glycoprotein (MAG)3,4, exert their effects through the same Nogo receptor (NgR). The glycosyl phosphatidylinositol (GPI)-anchored nature of NgR indicates the requirement for additional transmembrane protein(s) to transduce the inhibitory signals into the interior of responding neurons. Here, we demonstrate that p75, a transmembrane protein known to be a receptor for the neurotrophin family of growth factors5,6, specifically interacts with NgR. p75 is required for NgR-mediated signalling, as neurons from p75 knockout mice are no longer responsive to myelin and to each of the known NgR ligands. Blocking the p75–NgR interaction also reduces the activities of these inhibitors. Moreover, a truncated p75 protein lacking the intracellular domain, when overexpressed in primary neurons, attenuates the same set of inhibitory activities, suggesting that p75 is a signal transducer of the NgR–p75 receptor complex. Thus, interfering with p75 and its downstream signalling pathways may allow lesioned axons to overcome most of the inhibitory activities associated with central nervous system myelin.

P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp.

The cAMP cascade, including the cAMP response element-binding protein (CREB), is known to play an important role in neuronal survival and plasticity. Here the influence of this cascade on neurogenesis in adult hippocampus was determined. Activation of the cAMP cascade by administration of rolipram, an inhibitor of cAMP breakdown, increased the proliferation of newborn cells in adult mouse hippocampus. In addition, rolipram induction of cell proliferation resulted in mature granule cells that express neuronal-specific markers. Increased cell proliferation is accompanied by activation of CREB phosphorylation in dentate gyrus granule cells, suggesting a role for this transcription factor. This possibility is supported by studies demonstrating that cell proliferation is decreased in conditional transgenic mice that express a dominant negative mutant of CREB in hippocampus. The results suggest that the cAMP–CREB cascade could contribute to the actions of neurotransmitters and neurotrophic factors on adult neurogenesis.

https://www.jneurosci.org/content/jneuro/22/9/3673.full.pdf

Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein.

Axon regeneration in young adult mice lacking Nogo-A/B.

Inhibitory molecules associated with myelin and the glial scar limit axon regeneration in the adult central nervous system (CNS), but the underlying signaling mechanisms of regeneration inhibition are not fully understood. Here, we show that suppressing the kinase function of the epidermal growth factor receptor (EGFR) blocks the activities of both myelin inhibitors and chondroitin sulfate proteoglycans in inhibiting neurite outgrowth. In addition, regeneration inhibitors trigger the phosphorylation of EGFR in a calcium-dependent manner. Local administration of EGFR inhibitors promotes significant regeneration of injured optic nerve fibers, pointing to a promising therapeutic avenue for enhancing axon regeneration after CNS injury.

https://science.sciencemag.org/content/sci/310/5745/106.full.pdf

Jieun Kim

Papers

Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth.

P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp.

Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein.

Axon regeneration in young adult mice lacking Nogo-A/B.

EGFR Activation Mediates Inhibition of Axon Regeneration by Myelin and Chondroitin Sulfate Proteoglycans