scholarly journals Multivesicular bodies mediate long-range retrograde NGF-TrkA signaling

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Mengchen Ye ◽  
Kathryn M Lehigh ◽  
David D Ginty
Keyword(s):  
Nervous System ◽  
Nerve Growth Factor ◽  
Long Range ◽  
Kinase Activity ◽  
Sympathetic Neurons ◽  
Membrane Vesicles ◽  
Multivesicular Bodies ◽  
Cell Soma ◽  
Early Endosomes ◽  
Prevailing View

The development of neurons in the peripheral nervous system is dependent on target-derived, long-range retrograde neurotrophic factor signals. The prevailing view is that target-derived nerve growth factor (NGF), the prototypical neurotrophin, and its receptor TrkA are carried retrogradely by early endosomes, which serve as TrkA signaling platforms in cell bodies. Here, we report that the majority of retrograde TrkA signaling endosomes in mouse sympathetic neurons are ultrastructurally and molecularly defined multivesicular bodies (MVBs). In contrast to MVBs that carry non-TrkA cargoes from distal axons to cell bodies, retrogradely transported TrkA+ MVBs that arrive in cell bodies evade lysosomal fusion and instead evolve into TrkA+ single-membrane vesicles that are signaling competent. Moreover, TrkA kinase activity associated with retrogradely transported TrkA+ MVBs determines TrkA+ endosome evolution and fate. Thus, MVBs deliver long-range retrograde NGF signals and serve as signaling and sorting platforms in the cell soma, and MVB cargoes dictate their vesicular fate.

scholarly journals Immunohistochemical analysis of nerve growth factor receptor expression in normal and malignant human tissues.

1988 ◽  
Vol 36 (4) ◽  
pp. 383-389 ◽  
Author(s):  
P G Chesa ◽  
W J Rettig ◽  
T M Thomson ◽  
L J Old ◽  
M R Melamed
Keyword(s):  
Nervous System ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Normal Development ◽  
Malignant Tumors ◽  
Sympathetic Neurons ◽  
Growth Factor Receptor ◽  
Nerve Growth Factor Receptor ◽  
Receptor Expression ◽  
Nerve Growth

Nerve growth factor (NGF) is a polypeptide important for normal development of the nervous system and promotion of survival and differentiation of sensory and sympathetic neurons in culture. The cellular effects of NGF are mediated by a specific cell surface molecule, nerve growth factor receptor (NGF-R). In the present study we have used a monoclonal antibody against human NGF-R to examine, by the avidin-biotin-immunoperoxidase method, the receptor distribution in a wide range of normal tissues and in more than 200 malignant tumors. Our results show that (a) human NGF-R is expressed in the peripheral nervous system but not in any of the central nervous system areas tested; (b) NGF-R expression is not restricted to neural tissues but is also found in a number of normal epithelial, mesenchymal, and lymphoid tissues; (c) NGF-R expression changes during normal development; and (d) NGF-R expression in malignant tumors generally parallels its normal tissue distribution. Thus, NGF-R is detected in a proportion of neuroectoderm-derived tumors, carcinomas, and lymphomas, and also in a characteristic group of small round-cell tumors (Ewing's sarcomas and embryonal rhabdomyosarcomas). These findings suggest a normal regulatory role for NGF in both neuronal and non-neuronal cells and identify a range of human tumors in which the NGF/NGF-R system may contribute to the malignant phenotype.

mKlf7, a potential transcriptional regulator of TrkA nerve growth factor receptor expression in sensory and sympathetic neurons

Development ◽  
2001 ◽  
Vol 128 (7) ◽  
pp. 1147-1158 ◽  
Author(s):  
L. Lei ◽  
L. Ma ◽  
S. Nef ◽  
T. Thai ◽  
L.F. Parada
Keyword(s):  
Nervous System ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Sympathetic Neurons ◽  
Growth Factor Receptor ◽  
Regulatory Elements ◽  
Receptor Expression ◽  
Expression Library ◽  
Nerve Growth

Development of the nervous system relies on stringent regulation of genes that are crucial to this process. TrkA, the receptor for nerve growth factor (NGF), is tightly regulated during embryonic development and is essential for the survival and differentiation of neural crest-derived sensory and sympathetic neurons. We have previously identified a mouse TrkA enhancer and have characterized several cis regulatory elements that are important for appropriate TrkA expression in vivo. We now report the cloning of a novel gene encoding a Kruppel-like factor from a mouse dorsal root ganglion expression library. This Kruppel-like factor, named mKlf7, binds specifically to an Ikaros core binding element that is crucial for in vivo TrkA enhancer function. Using in situ hybridization, we demonstrate that mKlf7 is coexpressed with TrkA in sensory and sympathetic neurons during embryogenesis and in adulthood. These data are consistent with the idea that mKlf7 may directly regulate TrkA gene expression in the peripheral nervous system.

scholarly journals Pro-Nerve Growth Factor Induces Activation of RhoA Kinase and Neuronal Cell Death

2019 ◽  
Vol 9 (8) ◽  
pp. 204 ◽  
Author(s):  
Marina Sycheva ◽  
Jake Sustarich ◽  
Yuxian Zhang ◽  
Vaithinathan Selvaraju ◽  
Thangiah Geetha ◽  
...  
Keyword(s):  
Cell Death ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Neuronal Cell Death ◽  
Rho Kinase ◽  
Neuronal Cell ◽  
Nerve Growth ◽  
Rhoa Kinase

We have previously shown that the expression of pro-nerve growth factor (proNGF) was significantly increased, nerve growth factor (NGF) level was decreased, and the expression of p75NTR was enhanced in Alzheimer’s disease (AD) hippocampal samples. NGF regulates cell survival and differentiation by binding TrkA and p75NTR receptors. ProNGF is the precursor form of NGF, binds to p75NTR, and induces cell apoptosis. The objective of this study is to determine whether the increased p75NTR expression in AD is due to the accumulation of proNGF and Rho kinase activation. PC12 cells were stimulated with either proNGF or NGF. Pull-down assay was carried out to determine the RhoA kinase activity. We found the expression of p75NTR was enhanced by proNGF compared to NGF. The proNGF stimulation also increased the RhoA kinase activity leading to apoptosis. The expression of active RhoA kinase was found to be increased in human AD hippocampus compared to control. The addition of RhoA kinase inhibitor Y27632 not only blocked the RhoA kinase activity but also reduced the expression of p75NTR receptor and inhibited the activation of JNK and MAPK induced by proNGF. This suggests that overexpression of proNGF in AD enhances p75NTR expression and activation of RhoA, leading to neuronal cell death.

scholarly journals Oligomerization and endocytosis of Hedgehog is necessary for its efficient exovesicular secretion

2015 ◽  
Vol 26 (25) ◽  
pp. 4700-4717 ◽  
Author(s):  
Anup Parchure ◽  
Neha Vyas ◽  
Charles Ferguson ◽  
Robert G. Parton ◽  
Satyajit Mayor
Keyword(s):  
Cell Surface ◽  
Long Range ◽  
Imaginal Discs ◽  
Multivesicular Bodies ◽  
Selective Effect ◽  
Endosomal Sorting ◽  
Drosophila Wing ◽  
Dependent Process ◽  
Wing Imaginal Discs ◽  
Hh Signaling

Hedgehog (Hh) is a secreted morphogen involved in both short- and long-range signaling necessary for tissue patterning during development. It is unclear how this dually lipidated protein is transported over a long range in the aqueous milieu of interstitial spaces. We previously showed that the long-range signaling of Hh requires its oligomerization. Here we show that Hh is secreted in the form of exovesicles. These are derived by the endocytic delivery of cell surface Hh to multivesicular bodies (MVBs) via an endosomal sorting complex required for transport (ECSRT)–dependent process. Perturbations of ESCRT proteins have a selective effect on long-range Hh signaling in Drosophila wing imaginal discs. Of importance, oligomerization-defective Hh is inefficiently incorporated into exovesicles due to its poor endocytic delivery to MVBs. These results provide evidence that nanoscale organization of Hh regulates the secretion of Hh on ESCRT-derived exovesicles, which in turn act as a vehicle for long-range signaling.

scholarly journals Aurintricarboxylic acid rescues PC12 cells and sympathetic neurons from cell death caused by nerve growth factor deprivation: correlation with suppression of endonuclease activity.

1991 ◽  
Vol 115 (2) ◽  
pp. 461-471 ◽  
Author(s):  
A Batistatou ◽  
L A Greene
Keyword(s):  
Cell Death ◽  
Nerve Growth Factor ◽  
Pc12 Cells ◽  
Sympathetic Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Endonuclease Activity ◽  
Term Survival ◽  
Serum Free

Past studies have shown that serum-free cultures of PC12 cells are a useful model system for studying the neuronal cell death which occurs after neurotrophic factor deprivation. In this experimental paradigm, nerve growth factor (NGF) rescues the cells from death. It is reported here that serum-deprived PC12 cells manifest an endonuclease activity that leads to internucleosomal cleavage of their cellular DNA. This activity is detected within 3 h of serum withdrawal and several hours before any morphological sign of cell degeneration or death. NGF and serum, which promote survival of the cells, inhibit the DNA fragmentation. Aurintricarboxylic acid (ATA), a general inhibitor of nucleases in vitro, suppresses the endonuclease activity and promotes long-term survival of PC12 cells in serum-free cultures. This effect appears to be independent of macromolecular synthesis. In addition, ATA promotes long-term survival of cultured sympathetic neurons after NGF withdrawal. ATA neither promotes nor maintains neurite outgrowth. It is hypothesized that the activation of an endogenous endonuclease could be responsible for neuronal cell death after neurotrophic factor deprivation and that growth factors could promote survival by leading to inhibition of constitutively present endonucleases.

Nerve Growth Factor Regulates the Expression of Brain-Derived Neurotrophic Factor mRNA in the Peripheral Nervous System

1996 ◽  
Vol 7 (2) ◽  
pp. 134-142 ◽  
Author(s):  
Stuart C. Apfel ◽  
Douglas E. Wright ◽  
Andrea M. Wiideman ◽  
Christine Dormia ◽  
William D. Snider ◽  
...  
Keyword(s):  
Nervous System ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Peripheral Nervous System ◽  
Neurotrophic Factor ◽  
Brain Derived Neurotrophic Factor ◽  
Nerve Growth

Analysis of the development of the nervous system of the zebrafish, Brachydanio rerio

Development ◽  
1968 ◽  
Vol 19 (2) ◽  
pp. 109-119
Author(s):  
Judith Shulman Weis
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
Neural Crest ◽  
Neural Tube ◽  
Sympathetic Neurons ◽  
Dorsal Surface ◽  
Teleost Fishes ◽  
Brachydanio Rerio ◽  
Solid Structure ◽  
Derivatives Of

In teleost fishes, unlike many other vertebrates, the spinal cord originates as a solid structure, the neural keel, which subsequently hollows out. Unlike vertebrates in which the neural tube is formed from neural folds, and where the neural crest arises from wedge-shaped masses of tissue connecting the neural tube to the general ectoderm, teleosts do not possess a clear morphological neural crest. Initially, the dorsal surface of the keel is broadly attached to the ectoderm as described by Shepard (1961). As the neural primordia become larger and more discrete, the region of attachment narrows, and cells become loose (the ‘loose crest stage’). These cells represent the neural crest. Subsequently they begin to migrate and to differentiate into the various derivatives of neural crest. Both sensory and sympathetic neurons arise from neural crest. At the time of their migration the cells are not morphologically distinguishable.

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