Thrombospondin 1 - A key astrocyte-derived neurogenic factor
Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.The FASEB Journal (Impact Factor: 5.04). 06/2010; 24(6):1925-34. DOI: 10.1096/fj.09-150573
Thrombospondin 1 (TSP1), an oligomeric matrix protein, is known for its antiangiogenic activity. Recently, TSP1 has been shown to regulate synaptogenesis in the developing brain. In this study, we examine another role of TSP1 in the CNS, namely, in proliferation and differentiation of neural progenitor cells (NPCs). We found that adult mice deficient in TSP1 exhibit reduced proliferation of NPCs in vivo [13,330+/-826 vs. 4914+/-455 (mean+/-se wt vs. TSP1(-/-)); P<0.001, Student's t test] and impaired neuronal differentiation (1382+/-83 vs. 879+/-79; P<0.001). In vitro, NPC obtained from adult TSP1(-/-) mice display decreased proliferation in BrdU assay (48+/-8 vs. 24+/-3.5%; P<0.01) and decreased neuronal fate commitment (8+/-0.85 vs. 4.6+/-0.5%; P<0.05) in contrast to wild-type NPCs. Both proliferation and neuronal differentiation deficits are remediable in vitro by exogenous TSP1. Notably, conditioned medium from TSP1(-/-) astrocytes, unlike that from control astrocytes, fails to promote neurogenesis in wild-type NPCs, suggesting that TSP1 is one of the key molecules responsible for astrocyte-induced neurogenesis. Our data demonstrate that TSP1 is a critical participant in maintenance of the adult NPC pool and in neuronal differentiation.
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- "The Notch signaling pathway is involved in cell fate decisions during development as well as in the neurogenic niches in the adult CNS. Activation of Notch signaling can promote neural progenitor cell differentiation into glial cells (Givogri et al. 2006), decrease neuronal differentiation and proliferation (Chambers et al. 2001) and is also involved in maintaining the undifferentiated neural stem/progenitor cell pool (Breunig et al. 2007; Ables et al. 2010; Ehm et al. 2010; Imayoshi et al. 2010; Lugert et al. 2010). Cross-talk with other signaling pathways is necessary to regulate the maintenance of the neural stem cell pool, gliogenesis, and neurogenesis (for review see, Zhou et al. 2010). "
ABSTRACT: Astrocytes have multiple roles in the CNS including control of adult neurogenesis. We recently showed that astrocyte inhibition of neurogenesis through Notch signaling depends on the intermediate filament proteins GFAP and vimentin. Here, we used real-time quantitative PCR to analyze gene expression in individual mouse astrocytes in primary cultures and in GFAP(POS) or Aldh1L1(POS) astrocytes freshly isolated from uninjured, contralesional and lesioned hippocampus 4 days after entorhinal cortex lesion. To determine the Notch signaling competence of individual astrocytes, we measured the mRNA levels of Notch ligands and Notch1 receptor. We found that whereas most cultured and freshly isolated astrocytes were competent to receive Notch signals, only a minority of astrocytes were competent to send Notch signals. Injury increased the fraction of astrocyte subpopulation unable to send and receive Notch signals, thus resembling primary astrocytes in vitro. Astrocytes deficient of GFAP and vimentin showed decreased Notch signal-sending competence and altered expression of Notch signaling pathway-related genes Dlk2, Notch1 and Sox2. Further, we identified astrocyte subpopulations based on their mRNA and protein expression of nestin and HB-EGF. This study improves our understanding of astrocyte heterogeneity, and points to astrocyte cytoplasmic intermediate filaments as targets for neural cell replacement strategies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Journal of Neurochemistry 06/2015; 135(2). DOI:10.1111/jnc.13213 · 4.28 Impact Factor
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- "theroleofNPYinthemodulationofanothersignalingpathway drivingacomplexmodulationofNSCactivitiesemerges.Itiswell known,infact,thatNOexertsadualinfluenceonneurogenesis, dependingonthesource(forreviewseeCarreiraetal.,2012): whileintracellularNOispro-neurogenic,theextracellularform exertsanegativeeffect(Luoetal.,2010).InthisrespecttheY1R hasalsobeenproposedasakeytargetintheselectivepromotion ofNO-mediatedenhancementofdentateneurogenesis(Cheung etal.,2012). Decressacetal.confirmed,byinvivoadministrationof exogenousNPYinbothwildtypeandY1Rknockoutmice, thatNPY-sensitivecellsarethetransitamplifyingprogenitors expressingnestinanddoublecortin(DCX),whichselectively expresstheY1R(Decressacetal.,2011),asalsoevidencedin "
ABSTRACT: Neuropeptides are emerging as key regulators of stem cell niche activities in health and disease, both inside and outside the central nervous system (CNS). Among them, neuropeptide Y (NPY), one of the most abundant neuropeptides both in the nervous system and in non-neural districts, has become the focus of much attention for its involvement in a wide range of physiological and pathological conditions, including the modulation of different stem cell activities. In particular, a pro-neurogenic role of NPY has been evidenced in the neurogenic niche, where a direct effect on neural progenitors has been demonstrated, while different cellular types, including astrocytes, microglia and endothelial cells, also appear to be responsive to the peptide. The marked modulation of the NPY system during several pathological conditions that affect neurogenesis, including stress, seizures and neurodegeneration, further highlights the relevance of this peptide in the regulation of adult neurogenesis. In view of the considerable interest in understanding the mechanisms controlling neural cell fate, this review aims to summarize and discuss current data on NPY signaling in the different cellular components of the neurogenic niche in order to elucidate the complexity of the mechanisms underlying the modulatory properties of this peptide.Frontiers in Cellular Neuroscience 03/2015; 9:85. DOI:10.3389/fncel.2015.00085 · 4.29 Impact Factor
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- "2002 ) . TSP - 1 expression was identified in post - natal and young adult animal brains ( Lu and Kipnis 2010 ; Yonezawa et al . 2010 ) , as well as in normal human cortical astrocytes ( Asch et al . "
ABSTRACT: Chronic hepatic encephalopathy (CHE) is a major complication in patients with severe liver disease. Elevated blood and brain ammonia levels have been implicated in its pathogenesis, and astrocytes are the principal neural cells involved in this disorder. Since defective synthesis and release of astrocytic factors have been shown to impair synaptic integrity in other neurological conditions, we examined whether thrombospondin-1 (TSP-1), an astrocytic factor involved in the maintenance of synaptic integrity, is also altered in CHE. Cultured astrocytes were exposed to ammonia (NH4Cl, 0.5-2.5 mM) for 1-10 days, and TSP-1 content was measured in cell extracts and culture media. Astrocytes exposed to ammonia exhibited a reduction in intra- and extracellular TSP-1 levels. Exposure of cultured neurons to conditioned media (CM) from ammonia-treated astrocytes showed a decrease in synaptophysin, PSD95 and synaptotagmin levels. CM from TSP-1 overexpressing astrocytes that were treated with ammonia, when added to cultured neurons, reversed the decline in synaptic proteins. Recombinant TSP-1 similarly reversed the decrease in synaptic proteins. Metformin, an agent known to increase TSP-1 synthesis in other cell types also reversed the ammonia-induced TSP-1 reduction. Likewise, we found a significant decline in TSP-1 level in cortical astrocytes, as well as a reduction in synaptophysin content in vivo in a rat model of CHE. These findings suggest that TSP-1 may represent an important therapeutic target for CHE.This article is protected by copyright. All rights reserved.Journal of Neurochemistry 07/2014; 131(3). DOI:10.1111/jnc.12810 · 4.28 Impact Factor
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