proNGF/NGF mixtures induce gene expression changes in PC12 cells that neither singly produces

Arisi, Ivan; D’Onofrio, Mara; Brandi, Rossella; Malerba, Francesca; Paoletti, Francesca; Storti, Andrea Ennio; Florenzano, Fulvio; Fasulo, Luisa; Cattaneo, Antonino

doi:10.1186/1471-2202-15-48

Cited by 11 publications

(12 citation statements)

References 33 publications

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“…9 ). Thus, upon co-administration we observed for proNGF a reduction both in the flux of vesicles and in the number of neurotrophins per vesicle that might stem from competition with NGF or from signaling events caused by NGF and proNGF simultaneous administration (see Discussion for more details) 7 .…”

Section: Resultsmentioning

confidence: 71%

“…Thus another possibility is that NGF, rather than being a simple competitor of proNGF for TrkA receptor binding, activates some signalling pathway that prevents proNGF to internalize. It is useful to recall here that different proNGF/NGF mixtures exert a signalling profile that is different from that raised separately by the two neurotrophins and that depends on the ratio between the two proteins 7 . In any case, whatever the competition mechanism, the most important finding emerging from these data is that proNGF retrograde signalling, which is likely to be pro-apoptotic, can emerge more when an NGF trophic signalling is absent.…”

Section: Discussionmentioning

confidence: 99%

“…This molecular switch relies on the different receptor binding profiles, determining different biological outcomes. When administered separately or together, NGF and proNGF activate distinct and peculiar gene expression patterns in target cells 6 7 . Disruption of the NGF to proNGF balance has been causally linked to neurodegeneration 8 9 , and the proNGF versus NGF ratio is increased in the cortex of Alzheimer’s disease patients 5 .…”

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confidence: 99%

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Precursor and mature NGF live tracking: one versus many at a time in the axons

Nadai

Marchetti

Rienzo

et al. 2016

Sci Rep

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The classical view of nerve growth factor (NGF) action in the nervous system is linked to its retrograde axonal transport. However, almost nothing is known on the trafficking properties of its unprocessed precursor proNGF, characterized by different and generally opposite biological functions with respect to its mature counterpart. Here we developed a strategy to fluorolabel both purified precursor and mature neurotrophins (NTs) with a controlled stoichiometry and insertion site. Using a single particle tracking approach, we characterized the axonal transport of proNGF versus mature NGF in living dorsal root ganglion neurons grown in compartmentalized microfluidic devices. We demonstrate that proNGF is retrogradely transported as NGF, but with a lower flux and a different distribution of numbers of neurotrophins per vesicle. Moreover, exploiting a dual-color labelling technique, we analysed the transport of both NT forms when simultaneously administered to the axon tips.

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Section: Resultsmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Precursor and mature NGF live tracking: one versus many at a time in the axons

Nadai

Marchetti

Rienzo

et al. 2016

Sci Rep

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“…This underscores the importance that in vivo proNGF and mature NGF coexist and their ratios are subject to a complex homeostatic regulation . Moreover, proNGF and NGF mixtures can exert actions that neither exerts alone . WT hippocampal NSCs proliferate less than AD11 but, unlike the latter, produce mature differentiated new βIII‐Tub + neurons.…”

Section: Discussionmentioning

confidence: 92%

ProNGF Is a Cell-Type-Specific Mitogen for Adult Hippocampal and for Induced Neural Stem Cells

et al. 2019

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The role of proNGF, the precursor of nerve growth factor (NGF), in the biology of adult neural stem cells (aNSCs) is still unclear. Here, we analyzed adult hippocampal neurogenesis in AD11 transgenic mice, in which the constitutive expression of anti-NGF antibody leads to an imbalance of proNGF over mature NGF. We found increased proliferation of progenitors but a reduced neurogenesis in the AD11 dentate gyrus (DG)-hippocampus (HP). Also in vitro, AD11 hippocampal neural stem cells (NSCs) proliferated more, but were unable to differentiate into morphologically mature neurons. By treating wild-type hippocampal progenitors with the uncleavable form of proNGF (proNGF-KR), we demonstrated that proNGF acts as mitogen on aNSCs at low concentration. The mitogenic effect of proNGF was specifically addressed to the radial glia-like (RGL) stem cells through the induction of cyclin D1 expression. These cells express high levels of p75 NTR , as demonstrated by immunofluorescence analyses performed ex vivo on RGL cells isolated from freshly dissociated HP-DG or selected in vitro from NSCs by leukemia inhibitory factor. Clonogenic assay performed in the absence of mitogens showed that RGLs respond to proNGF-KR by reactivating their proliferation and thus leading to neurospheres formation. The mitogenic effect of proNGF was further exploited in the expansion of mouse-induced neural stem cells (iNSCs). Chronic exposure of iNSCs to proNGF-KR increased their proliferation. Altogether, we demonstrated that proNGF acts as mitogen on hippocampal and iNSCs. STEM CELLS 2019;37:1223-1237 SIGNIFICANCE STATEMENTTo the authors' knowledge, this work identifies for the first time a new role of proNGF as a specific mitogenic factor for the proliferation of adult hippocampal neural stem cells and in induced neural stem cells. The relevance of this finding is that it adds new knowledge to the complex picture of neural stem cells biology and indicates proNGF/NGF balance critical for adult hippocampal neurogenesis. In addition, the results open new perspectives in the view of developing future therapeutic approaches based on the stimulation of endogenous adult neurogenesis or on cell-reprogramming protocols.Stereological analysis of the number of cells was performed on series of 40-μm free-floating coronal sections of the entire DG of the HP, which were analyzed by confocal microscopy to www.StemCells.com

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“…The robust transcriptional effects of NGF are well-characterized (Dijkmans et al, 2009 ). More recent data show that proNGF activates a largely distinct transcriptional program, and is a less potent transcriptional activator, compared to NGF, in target cells in vitro (D'Onofrio et al, 2011 ); moreover the extent of NGF/proNGF imbalance, affects the transcriptional outcome (Arisi et al, 2014 ). Therefore, a parallel analysis of early transcriptional changes in transgenic mice hippocampus was performed, in order to gain further insights into the mechanism starting and sustaining TgproNGF#3 mice phenotype.…”

Section: Introductionmentioning

confidence: 99%

ProNGF Drives Localized and Cell Selective Parvalbumin Interneuron and Perineuronal Net Depletion in the Dentate Gyrus of Transgenic Mice

Fasulo

Brandi

Arisi

et al. 2017

Front. Mol. Neurosci.

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ProNGF, the precursor of mature Nerve Growth Factor (NGF), is the most abundant NGF form in the brain and increases markedly in the cortex in Alzheimer's Disease (AD), relative to mature NGF. A large body of evidence shows that the actions of ProNGF and mature NGF are often conflicting, depending on the receptors expressed in target cells. TgproNGF#3 mice, expressing furin-cleavage resistant proNGF in CNS neurons, directly reveal consequences of increased proNGF levels on brain homeostasis. Their phenotype clearly indicates that proNGF can be a driver of neurodegeneration, including severe learning and memory behavioral deficits, cholinergic deficits, and diffuse immunoreactivity for A-beta and A-beta-oligomers. In aged TgproNGF#3 mice spontaneous epileptic-like events are detected in entorhinal cortex-hippocampal slices, suggesting occurrence of excitatory/inhibitory (E/I) imbalance. In this paper, we investigate the molecular events linking increased proNGF levels to the epileptiform activity detected in hippocampal slices. The occurrence of spontaneous epileptiform discharges in the hippocampal network in TgproNGF#3 mice suggests an impaired inhibitory interneuron homeostasis. In the present study, we detect the onset of hippocampal epileptiform events at 1-month of age. Later, we observe a regional- and cellular-selective Parvalbumin interneuron and perineuronal net (PNN) depletion in the dentate gyrus (DG), but not in other hippocampal regions of TgproNGF#3 mice. These results demonstrate that, in the hippocampus, the DG is selectively vulnerable to altered proNGF/NGF signaling. Parvalbumin interneuron depletion is also observed in the amygdala, a region strongly connected to the hippocampus and likewise receiving cholinergic afferences. Transcriptome analysis of TgproNGF#3 hippocampus reveals a proNGF signature with broad down-regulation of transcription. The most affected mRNAs modulated at early times belong to synaptic transmission and plasticity and extracellular matrix (ECM) gene families. Moreover, alterations in the expression of selected BDNF splice variants were observed. Our results provide further mechanistic insights into the vicious negative cycle linking proNGF and neurodegeneration, confirming the regulation of E/I homeostasis as a crucial mediating mechanism.

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proNGF/NGF mixtures induce gene expression changes in PC12 cells that neither singly produces

Cited by 11 publications

References 33 publications

Precursor and mature NGF live tracking: one versus many at a time in the axons

Precursor and mature NGF live tracking: one versus many at a time in the axons

ProNGF Is a Cell-Type-Specific Mitogen for Adult Hippocampal and for Induced Neural Stem Cells

ProNGF Drives Localized and Cell Selective Parvalbumin Interneuron and Perineuronal Net Depletion in the Dentate Gyrus of Transgenic Mice

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