Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport

Ding, Jingzhong; Allen, Elizabeth; Wang, Wei; Valle, Angela; Wu, Chengbiao; Nardine, Timothy; Cui, Bianxiao; Yi, Jongheop; Taylor, Anne Marion; Jeon, Noo Li; Chu, Steven; So, Yuen T.; Vogel, Hannes; Tolwani, Ravi; Mobley, William C.; Yang, Yanmin

doi:10.1093/hmg/ddl069

Cited by 77 publications

(99 citation statements)

References 32 publications

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“…The ''blinking'' property and electron-dense core of QDs led to the surprising discovery that most endosomes carried a single NGF dimer at physiological concentrations. In view of recent findings revealing impaired NGF transport in mouse models of giant axonal neuropathy (40,41) and Down syndrome (42), these technologies may well facilitate studies of those systems in which failed NGF transport contributes to neurodegeneration.…”

Section: Discussionmentioning

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.

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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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Section: Discussionmentioning

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.

Self Cite

338

336

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“…Despite the modest phenotypic manifestation and no pronounced signs of neurodegeneration, these mice exhibited severe cytoskeletal alterations, including an increase in the diameter of NFs, an overt impairment in their orientation and a strikingly increased abundance of the three NF subunits. Finally, they tested motor deficits in GAN Δ3-5 mice produced by Ding et al [114] and detected no clinical signs within the first year. This is consistent with a mild progression of the disease in mice and suggests that the three existing models probably display a phenotype of similar intensity.…”

Section: Giant Axonal Neuropathymentioning

confidence: 99%

“…In order to determine how loss of gigaxonin's function leads to GAN, mice deleted in exons 3-5 of the GAN gene (GAN Δ3-5 mice) were produced [114]. These mice develop strong motor deficits as early as 6 months of age, including reduction of spontaneous movement, bizarre limb posture and overall weakness.…”

Section: Giant Axonal Neuropathymentioning

confidence: 99%

“…Moreover, increased levels of neuronal IF proteins were detected in various regions of the nervous system, confirming the importance of gigaxonin in modulating the levels and organization of IF proteins. Given the very different phenotypes between these two GAN models, Ganay et al [117] conducted a behavioral analysis over a 72-week period in their own GAN Δ3-5 mice as well as in GAN Δ3-5 mice developed by Ding et al [114]. Analysis performed on their own model revealed difference depending on the genetic background.…”

Section: Giant Axonal Neuropathymentioning

confidence: 99%

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Intermediate Filaments in Neurodegenerative Diseases

Perrot¹,

Eyer²

2013

Neurodegenerative Diseases

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“…No developmental or behavioral defects have been observed in MAP1S-deficient mice (Xie et al 2011). However, high levels of MAP1S cause excessive MT stabilization, disrupt axonal transport, and lead to neuronal death (Ding et al 2006a). …”

Section: Map1 Family Member Map1smentioning

confidence: 99%

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

2016

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Dendrites have a unique microtubule organization. In vertebrates, dendritic microtubules are organized in antiparallel bundles, oriented with their plus ends either pointing away or toward the soma. The mixed microtubule arrays control intracellular trafficking and local signaling pathways, and are essential for dendrite development and function. The organization of microtubule arrays largely depends on the combined function of different microtubule regulatory factors or generally named microtubule-associated proteins (MAPs). Classical MAPs, also called structural MAPs, were identified more than 20 years ago based on their ability to bind to and copurify with microtubules. Most classical MAPs bind along the microtubule lattice and regulate microtubule polymerization, bundling, and stabilization. Recent evidences suggest that classical MAPs also guide motor protein transport, interact with the actin cytoskeleton, and act in various neuronal signaling networks. Here, we give an overview of microtubule organization in dendrites and the role of classical MAPs in dendrite development, dendritic spine formation, and synaptic plasticity. IntroductionMicrotubules (MTs) are cytoskeletal structures that play essential roles in all eukaryotic cells. MTs are important not only during cell division but also in non-dividing cells, where they are critical structures in numerous cellular processes such as cell motility, migration, differentiation, intracellular transport and organelle positioning. MTs are composed of two proteins, α-and β-tubulin, that form heterodimers and organize themselves in a head-to-tail manner. MTs are dynamic and they can rapidly switch between cycles of growth and shrinkage. This MT

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Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport

Cited by 77 publications

References 32 publications

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

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

Intermediate Filaments in Neurodegenerative Diseases

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

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