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Ahn, S. & Joyner, A.L. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437, 894-897

Howard Hughes Medical Institute, Developmental Genetics Program, Skirball Institute of Biomolecular Medicine and Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.
Nature (Impact Factor: 41.46). 11/2005; 437(7060):894-7. DOI: 10.1038/nature03994
Source: PubMed

ABSTRACT

Sonic hedgehog (Shh) has been implicated in the ongoing neurogenesis in postnatal rodent brains. Here we adopted an in vivo genetic fate-mapping strategy, using Gli1 (GLI-Kruppel family member) as a sensitive readout of Shh activity, to systematically mark and follow the fate of Shh-responding cells in the adult mouse forebrain. We show that initially, only a small population of cells (including both quiescent neural stem cells and transit-amplifying cells) responds to Shh in regions undergoing neurogenesis. This population subsequently expands markedly to continuously provide new neurons in the forebrain. Our study of the behaviour of quiescent neural stem cells provides in vivo evidence that they can self-renew for over a year and generate multiple cell types. Furthermore, we show that the neural stem cell niches in the subventricular zone and dentate gyrus are established sequentially and not until late embryonic stages.

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    • "This indicates that adult neurogenesis may be able to enhance the GC-mediated negative feedback mechanism of the HPA axis and thus could eventually act as a buffer to stress. In addition, GCs acting on GRs can result in the modulation of gene transcription through several complex molecular pathways, some of which are also involved in neurogenesis, namely, the forkhead box protein O3 (FOXO3A) pathway, which is activated, and the transforming growth factor í µí»½ (TGFí µí»½)- SMAD2-SMAD3 pathway and the Hedgehog pathway, which are inhibited [29] [30] [31] [32] [33] [34]. Moreover, studies could show that stress also initiates the release of proinflammatory cytokines in the hippocampus and several other brain regions, where interleukin 1í µí»½ levels are increased through a catecholamine-mediated mechanism [35]. "
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    ABSTRACT: Extensive behavioural, pharmacological, and neurological research reports stress effects on mammalian memory processes. While stress effects on memory quantity have been known for decades, the influence of stress on multiple memory systems and their distinct contributions to the learning process have only recently been described. In this paper, after summarizing the fundamental biological aspects of stress/emotional arousal and recapitulating functionally and anatomically distinct memory systems, we review recent animal and human studies exploring the effects of stress on multiple memory systems. Apart from discussing the interaction between distinct memory systems in stressful situations, we will also outline the fundamental role of the amygdala in mediating such stress effects. Additionally, based on the methods applied in the herein discussed studies, we will discuss how memory translates into behaviour.
    Full-text · Article · Jan 2016
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    • "Prox1 staining of the dentate granule neurons showed more restricted localization of neurons in the upper blade of the mutant DG (Figure 2B). The decline of Ki67 + dentate progenitors in the Krt14-Cre;Shh flx/flx mutant coincides with the requirement of hedgehog signaling for the expansion of dentate stem cells just before birth (Ahn and Joyner, 2005). However, these straightforward data do not exclude indirect involvement of hair follicular Shh in the expansion of dentate progenitors. "
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    ABSTRACT: Dentate neural stem cells produce neurons throughout life in mammals. Sonic hedgehog (Shh) is critical for maintenance of these cells; however, the perinatal source of Shh is enigmatic. In the present study, we examined the role of Shh expressed by hair follicles (HFs) that expand perinatally in temporal concordance with the proliferation of Shh-responding dentate stem cells. Specific inhibition of Shh from HFs or from epithelial sources in general hindered development of Shh-responding dentate stem cells. We also found that the blood-brain barrier (BBB) of the perinatal dentate gyrus (DG) is leaky with stem cells in the dentate exposed to blood-born factors. In attempting to identify how Shh might be transported in blood, we found that platelets contain epithelial Shh, provide Shh to the perinatal DG and that inhibition of platelet generation reduced hedgehog-responsive dentate stem cells.
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    • "DCX is a microtubule-associated protein expressed in cells early after mitosis (Couillard- Despres et al., 2005) and which may be involved in disorders of neocortical and hippocampal development (Gleeson et al., 1999; Nacher et al., 2001; Corbo et al., 2002). Shh protein is important in the formation of morphogenetic gradients (Palma et al., 2005; Traiffort et al., 2010) and the generation of functional synaptic contacts (Angot et al., 2008; Hor and Tang, 2010) but it does persist in the adult CNS (Traiffort et al., 1998; Charytoniuk et al., 2002; Ahn and Joyner, 2005; Dellovade et al., 2006). "
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    ABSTRACT: Glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70kDa and 100kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(-/-) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development.
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