Neurotrophin-regulated signalling pathways Reichardt, Louis F
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
09/2006, Volume:
361, Issue:
1473
Journal Article
Peer reviewed
Open access
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-γ1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-κB (NF-κB) 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.
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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-γ
(PLC-γ). 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 p75
NTR
. p75
NTR
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.
p75
NTR
also influences the conformations of Trk receptors; this
modifies ligand-binding specificity and affinity with important developmental
consequences.
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CMK, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Synapse formation involves reciprocal interactions between cells resulting in formation of a structure optimized for efficient information transfer. Recent work has implicated constituents of the ...cadherin–catenin cell-adhesion complex in both synapse formation and plasticity. In this review, we describe recent interesting discoveries on mechanisms of cadherin complex function, in addition to regulating adhesion, that are relevant for understanding the role of this complex in synaptogenesis and plasticity. We describe how this complex acts via (i) recruitment/stabilization of intracellular partners; (ii) regulation of intracellular signaling pathways; (iii) regulation of cadherin surface levels, stability and turnover; (iv) stabilization of receptors; and (v) regulation of gene expression. These exciting discoveries provide insights into novel functional roles of the complex beyond regulating cell adhesion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The association of p120 catenin (p120) with the juxtamembrane domain (JMD) of the cadherin cytoplasmic tail is critical for the surface stability of cadherin-catenin cell-cell adhesion complexes. ...Here, we present the crystal structure of p120 isoform 4A in complex with the JMD core region (JMD
core) of E-cadherin. The p120 armadillo repeat domain contains modular binding pockets that are complementary to electrostatic and hydrophobic properties of the JMD
core. Single-residue mutations within the JMD
core-binding site of p120 abolished its interaction with E- and N-cadherins in vitro and in cultured cells. These mutations of p120 enabled us to clearly differentiate between N-cadherin-dependent and -independent steps of neuronal dendritic spine morphogenesis crucial for synapse development. NMR studies revealed that p120 regulates the stability of cadherin-mediated cell-cell adhesion by associating with the majority of the JMD, including residues implicated in clathrin-mediated endocytosis and Hakai-dependent ubiquitination of E-cadherin, through its discrete “dynamic” and “static” binding sites.
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► Crystal structure of p120 in complex with E-cadherin juxtamembrane domain ► Mutations in p120 confirm functional importance of its interface with cadherins ► Static p120 and E-cadherin interface is critical for high affinity interaction ► NMR reveals dynamic interactions that regulate the stability of cell-cell adhesion
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The four mammalian neurotrophins — NGF, BDNF, NT-3 and NT-4 — each bind and activate one or more of the Trk family of receptor tyrosine kinases. Through these receptors, neurotrophins activate many ...intracellular signaling pathways, including those controlled by Ras, the Cdc42/Rac/RhoG protein family, MAPK, PI3K and PLC-γ, thereby affecting both development and function of the nervous system. During the past two years, several novel signaling pathways controlled by Trk receptors have been characterized, and it has become clear that membrane transport and sorting controls Trk-receptor-mediated signaling because key intermediates are localized to different membrane compartments. Three-dimensional structures of the Trk receptors, in one instance in association with a neurotrophin, have revealed the structural bases underlying specificity in neurotrophin signaling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and ...p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Simons Foundation Autism Research Initiative (SFARI) has launched SPARKForAutism.org, a dynamic platform that is engaging thousands of individuals with autism spectrum disorder (ASD) and ...connecting them to researchers. By making all data accessible, SPARK seeks to increase our understanding of ASD and accelerate new supports and treatments for ASD.
The Simons Foundation Autism Research Initiative (SFARI) has launched SPARKForAutism.org, a dynamic platform that is engaging thousands of individuals with autism spectrum disorder (ASD) and connecting them to researchers. By making all data accessible, SPARK seeks to increase our understanding of ASD and accelerate new supports and treatments for ASD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The melanocortin-4 receptor (MC4R) is critically involved in regulating energy balance, and obesity has been observed in mice with mutations in the gene for brain-derived neurotrophic factor (BDNF). ...Here we report that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling. In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling. These results show that MC4R signaling controls BDNF expression in the VMH and support the hypothesis that BDNF is an important effector through which MC4R signaling controls energy balance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The ability to culture and maintain postnatal mouse hippocampal and cortical neurons is highly advantageous, particularly for studies on genetically engineered mouse models. Here we present a ...protocol to isolate and culture pyramidal neurons from the early postnatal (P0-P1) mouse hippocampus and cortex. These low-density dissociated cultures are grown on poly-L-lysine-coated glass substrates without feeder layers. Cultured neurons survive well, develop extensive axonal and dendritic arbors, express neuronal and synaptic markers, and form functional synaptic connections. Further, they are highly amenable to low- and high-efficiency transfection and time-lapse imaging. This optimized cell culture technique can be used to culture and maintain neurons for a variety of applications including immunocytochemistry, biochemical studies, shRNA-mediated knockdown and live imaging studies. The preparation of the glass substrate must begin 5 d before the culture. The dissection and plating out of neurons takes 3-4 h and neurons can be maintained in culture for up to 4 weeks.
The hair follicle bulge in the epidermis associates with the arrector pili muscle (APM) that is responsible for piloerection (“goosebumps”). We show that stem cells in the bulge deposit nephronectin ...into the underlying basement membrane, thus regulating the adhesion of mesenchymal cells expressing the nephronectin receptor, α8β1 integrin, to the bulge. Nephronectin induces α8 integrin-positive mesenchymal cells to upregulate smooth muscle markers. In nephronectin knockout mice, fewer arrector pili muscles form in the skin, and they attach to the follicle above the bulge, where there is compensatory upregulation of the nephronectin family member EGFL6. Deletion of α8 integrin also abolishes selective APM anchorage to the bulge. Nephronectin is a Wnt target; epidermal β-catenin activation upregulates epidermal nephronectin and dermal α8 integrin expression. Thus, bulge stem cells, via nephronectin expression, create a smooth muscle cell niche and act as tendon cells for the APM. Our results reveal a functional role for basement membrane heterogeneity in tissue patterning.
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► Stem cells in the hair follicle bulge express nephronectin, an ECM protein ► Deposition of nephronectin in the basement membrane creates a unique niche ► Nephronectin induces differentiation of arrector pili muscles, which cause “goosebumps” ► Arrector pili muscles attach to nephronectin; thus, bulge stem cells serve as tendons
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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