Pincher-Mediated Macroendocytosis Underlies Retrograde Signaling by Neurotrophin Receptors

Valdez, Gregorio; Akmentin, Wendy; Philippidou, Polyxeni; Kuruvilla, Rejji; Ginty, David D.; Halegoua, Simon

doi:10.1523/jneurosci.5104-04.2005

Cited by 131 publications

(150 citation statements)

References 46 publications

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“…In this study, internalized Trk-endosomes retain association with rab5, a small GTPase involved in the formation of the early endosome (Bucci et al 1992), which prevents maturation to rab7-positive late endosomes and degradation through the lysosomal pathway. Furthermore, the retention of rab5-positive endosomes promotes sustained NGF-stimulated signaling (Valdez et al 2005(Valdez et al , 2007. These data are consistent with another study performed on peripheral sensory neurons in which retrograde signaling of TrkA occurred in early endosomes (Delcroix et al 2003).…”

Section: Internalization and Retrograde Signalingsupporting

confidence: 89%

“…Various reports have demonstrated that retrograde signaling of Trk is required for survival of peripheral and central neurons in culture through the activation of ERK5, phosphorylation of the cAMP response element-binding protein, and the consequent initiation of gene transcription (Ye et al 2003;Heerssen et al 2004;Valdez et al 2005). Furthermore, retrograde signaling from dendrites of hippocampal neurons has been linked to long-term potentiation (Patterson et al 2001).…”

Section: Internalization and Retrograde Signalingmentioning

confidence: 99%

“…Furthermore, retrograde signaling from dendrites of hippocampal neurons has been linked to long-term potentiation (Patterson et al 2001). The mechanisms that regulate Trk retrograde signaling are still elusive; however, they are likely highly regulated, as this process must engage microtubule proteins, block the degradation or recycling of internalized receptors, and recruit the appropriate signaling complexes for neuronal survival (Valdez et al 2005). Recently, a unique mechanism for retrograde transport and signaling has been defined for TrkA in PC12 cells and primary hippocampal neurons, in which receptors are internalized within membrane ruffles independent of clathrin, a process termed macroendocytosis (Valdez et al 2007).…”

Section: Internalization and Retrograde Signalingmentioning

confidence: 99%

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Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

Romanelli

Wood²

2008

Journal of Neurochemistry

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The trafficking of receptor tyrosine kinases (RTKs) to distinct subcellular locations is essential for the specificity and fidelity of signal transduction and biological responses. This is particularly important in the PNS and CNS in which RTKs mediate key events in the development and maintenance of neurons and glia through a wide range of neural processes, including survival, proliferation, differentiation, neurite outgrowth, and synaptogenesis. The mechanisms that regulate the targeting of RTKs to their subcellular destinations for appropriate signal transduction, however, are still elusive. In this review, we discuss evidence for the spatial organization of signaling machinery into distinct subcellular compartments, as well as the role for ligand specificity, receptor sorting signals, and lipid raft microdomains in RTK targeting and the resultant cellular responses in neural cells.

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Section: Internalization and Retrograde Signalingsupporting

confidence: 89%

Section: Internalization and Retrograde Signalingmentioning

confidence: 99%

Section: Internalization and Retrograde Signalingmentioning

confidence: 99%

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Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

Romanelli

Wood²

2008

Journal of Neurochemistry

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“…One set of hypotheses for retrograde axonal transport of NGF states that NGF and its signaling proteins are transported in complex vesicles such as multivesicular bodies, lysosomes, or macropinosomes (8,20,36). To examine the endocytic compartment(s) that immediate the retrograde transport of QD-NGF, we took advantage of the fact that QD has an electron dense core that can be visualized under electron microscopy (EM) (37).…”

Section: Most Qd-ngf Is Transported In Axons In Small 50-to 150-nm Vementioning

confidence: 99%

One at a time, live tracking of NGF axonal transport using quantum dots

Cui¹,

Chen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

340

336

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Retrograde axonal transport of nerve growth factor (NGF) signals is critical for the survival, differentiation, and maintenance of peripheral sympathetic and sensory neurons and basal forebrain cholinergic neurons. However, the mechanisms by which the NGF signal is propagated from the axon terminal to the cell body are yet to be fully elucidated. To gain insight into the mechanisms, we used quantum dot-labeled NGF (QD-NGF) to track the movement of NGF in real time in compartmentalized culture of rat dorsal root ganglion (DRG) neurons. Our studies showed that active transport of NGF within the axons was characterized by rapid, unidirectional movements interrupted by frequent pauses. Almost all movements were retrograde, but short-distance anterograde movements were occasionally observed. Surprisingly, quantitative analysis at the single molecule level demonstrated that the majority of NGFcontaining endosomes contained only a single NGF dimer. Electron microscopic analysis of axonal vesicles carrying QD-NGF confirmed this finding. The majority of QD-NGF was found to localize in vesicles 50 -150 nm in diameter with a single lumen and no visible intralumenal membranous components. Our findings point to the possibility that a single NGF dimer is sufficient to sustain signaling during retrograde axonal transport to the cell body.live imaging ͉ nerve growth factor ͉ single molecule imaging ͉ NGF signaling ͉ retrograde transport N erve growth factor (NGF) is produced and released by target tissues to activate specific receptors at the axon terminals of innervating neurons. In order for NGF to regulate gene expression and the survival of target neurons, a signal must be moved a considerable distance, in some cases Ͼ1,000-fold the diameter of the neuron cell body. The elucidation of the mechanism(s) used to transmit NGF signal from the terminals of axons to cell bodies of neurons is yet to be fully defined. In that retrograde NGF signaling is critical for the survival and maintenance of neurons of both the peripheral and central nervous systems, and the underlying mechanisms are likely to be shared by related neurotrophic factors, the issue remains one of the most significant and intriguing questions in neurobiology (1-16).In the past, radio-labeled NGF ( 125 I-NGF) has been used to study the binding, internalization, and axonal transport of NGF. These studies facilitated the measurement of transport rate and provided insights into the endocytic pathways used for NGF transport (8,(16)(17)(18)(19). Fluorescent labels such as rhodamine (20), Texas red (21), and Cy3 (22) were also used to track NGF movement in neurons. However, because these previous methods have limited spatial and temporal resolution, they provide only a coarse look at what is expected to be a very dynamic process. Moreover, few studies have examined NGF-containing endosomes during axonal transit. Some have suggested that NGF is transported principally within early endosomes (4, 5, 7-14) whereas others suggest that NGF is transported in organelles with com...

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“…The signaling endosome model proposes that upon ligand binding and activation, Trk receptors at the distal axon are internalized via clathrin-mediated [12][13][14] or pincher-dependent endocytosis [15,16]. The resultant vesicles containing the ligand-receptor complex are retrogradely transported to the cell body in order to mediate a survival response [3,[7][8][9][10][11]17, 18].…”

Section: Retrograde Axonal Transport Mechanismsmentioning

confidence: 99%

Action in the axon: generation and transport of signaling endosomes

Cosker

Courchesne

Segal

2008

Current Opinion in Neurobiology

138

137

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Neurons extend axonal processes over long distances, necessitating efficient transport mechanisms to convey target-derived neurotrophic survival signals from remote distal axons to cell bodies. Retrograde transport, powered by dynein motors, supplies cell bodies with survival signals in the form of "signaling endosomes". In this review, we will discuss new advances in our understanding of the motor proteins that bind to and move signaling components in a retrograde direction, and discuss mechanisms that might specify distinct neuronal responses to spatially restricted neurotrophin signals. Disruption of retrograde transport leads to a variety of neurodegenerative diseases, highlighting the role of retrograde transport of signaling endosomes for axonal maintenance and the importance of efficient transport for neuronal survival and function. Retrograde axonal transport mechanismsNeurons extend long axons to contact post-synaptic targets far removed from the neuronal cell body. Hence long-range communication between the nerve ending and the cell body is essential for axonal pathfinding, target innervation, plasticity and survival. The neurotrophin family, including nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin 3 or 4 (NT-3 and NT-4), are well-characterized growth factors that are often produced in post-synaptic cells and initiate signals at axon terminals by binding specific Trk receptors [1,2]. How are these signals conveyed to the cell body in order to alter gene expression? Several lines of experiments indicate that transport by microtubule-dependent dynein motors transmit these long-range signals [3][4][5][6]. Although there exist alternative models [4,7,8], it is widely accepted that vesicular-based transport of a "signaling endosome" is required for many, if not most, aspects of retrograde signaling mechanisms and will be the focus of this review.In compartmentalized cultures of sensory and sympathetic neurons, activated phosphorylated Trks (P-Trks) accumulate in cell bodies upon distal axon exposure to neurotrophins [9][10][11]. The signaling endosome model proposes that upon ligand binding and activation, Trk receptors at the distal axon are internalized via clathrin-mediated [12][13][14] or pincher-dependent endocytosis [15,16]. The resultant vesicles containing the ligand-receptor complex are retrogradely transported to the cell body in order to mediate a survival response [3,[7][8][9][10][11]17, 18]. © 2008 Elsevier Ltd. All rights reserved.Corresponding author: Rosalind Segal (E-mail: rosalind_segal@dfci.harvard.edu), Phone (617) 632-4737; Fax (617) 632-2085. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered ...

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Pincher-Mediated Macroendocytosis Underlies Retrograde Signaling by Neurotrophin Receptors

Cited by 131 publications

References 46 publications

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

One at a time, live tracking of NGF axonal transport using quantum dots

Action in the axon: generation and transport of signaling endosomes

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