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


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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    • "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.
    eLife Sciences 10/2015; 4. DOI:10.7554/eLife.07834 · 9.32 Impact Factor
    • "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.
    Neuroscience 09/2015; 310. DOI:10.1016/j.neuroscience.2015.09.022 · 3.36 Impact Factor
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    • "Another lines of evidence indicate that neural progenitor cells respond to neuronal activity in the form of glutamate and GABA secretion as part of their differentiation program (Song et al., 2002; Deisseroth et al., 2004; Tozuka et al., 2005). In addition to these neurotransmitters , astrocytes are described also a potential source of niche factors such as Notch, Shh, bone morphogenetic proteins (BMPs), and Wnts (Ahn and Joyner, 2005; Lie et al., 2005; Ables et al., 2010; Mira et al., 2010). "
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    ABSTRACT: Neurogenesis-the generation of new neurons-is an ongoing process that persists in the adult mammalian brain of several species, including humans. In this work we analyze two discrete brain regions: the subventricular zone (SVZ) lining the walls of the lateral ventricles; and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus in mice and shed light on the SVZ and SGZ specific neurogenesis. We propose a computational model that relies on the construction and analysis of region specific gene regulatory networks (GRNs) from the publicly available data on these two regions. Using this model a number of putative factors involved in neuronal stem cell (NSC) identity and maintenance were identified. We also demonstrate potential gender and niche-derived differences based on cell surface and nuclear receptors via Ar, Hif1a, and Nr3c1. We have also conducted cell fate determinant analysis for SVZ NSC populations to Olfactory Bulb interneurons and SGZ NSC populations to the granule cells of the Granular Cell Layer. We report 31 candidate cell fate determinant gene pairs, ready to be validated. We focus on Ar-Pax6 in SVZ and Sox2-Ncor1 in SGZ. Both pairs are expressed and localized in the suggested anatomical structures as shown by in situ hybridization and found to physically interact. Finally, we conclude that there are fundamental differences between SGZ and SVZ neurogenesis. We argue that these regulatory mechanisms are linked to the observed differential neurogenic potential of these regions. The presence of nuclear and cell surface receptors in the region specific regulatory circuits indicate the significance of niche derived extracellular factors, hormones and region specific factors such as the oxygen sensitivity, dictating SGZ and SVZ specific neurogenesis.
    Frontiers in Cellular Neuroscience 12/2014; 8:437. DOI:10.3389/fncel.2014.00437 · 4.29 Impact Factor
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