Ahn, S. & Joyner, A.L. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437, 894-897
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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- "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). "
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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- "The Shh signaling pathway is important in the maintenance and proliferation of neural progenitor cells in adult rodent brains ( Ahn and Joyner , 2005 ; Palma et al . , 2005 ) . "
ABSTRACT: It is known that neurogenesis occurs throughout the life mostly in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle. We investigated whether neurogenesis occurred in the amygdala and its function in fear memory formation. For detection of newborn neurons, mice were injected intraperitoneally with 5-bromo-2'-deoxyuridine (BrdU) 2 h before receiving 15 tone-footshock pairings and newborn neurons were analyzed 14 and 42 days after training. To determine the relationship between neurogenesis and memory formation, mice were given a proliferation inhibitor methylazoxymethanol (MAM) or a DNA synthesis inhibitor cytosine arabinoside (Ara-C). To test whether Sonic hedgehog (Shh) signaling was required for neurogenesis, Shh-shRNA was inserted into a retroviral vector (Retro-Shh-shRNA). The number of BrdU(+)/NeuN(+) cells was significantly higher in the conditioned mice suggesting that association of tone with footshock induced neurogenesis. MAM and Ara-C markedly reduced neurogenesis and impaired fear memory formation. Sonic hedgehog (Shh), its receptor patched1 (Ptc1) and transcription factor Gli1 protein levels increased at 1 day and returned to baseline at 7 days after fear conditioning. Retro-Shh-shRNA which knocked down Shh specifically in the mitotic neurons reduced the number of BrdU(+)/NeuN(+) cells and decreased freezing responses. These results suggest that fear learning induces Shh signaling activation in the amygdala which promotes neurogenesis and fear memory formation. © The Author 2014. Published by Oxford University Press on behalf of CINP.The International Journal of Neuropsychopharmacology 12/2014; 18(3). DOI:10.1093/ijnp/pyu071 · 4.01 Impact Factor
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- "The importance of the critical and tight regulation of the GLI code is illustrated on the one hand by the fact that varying levels of HH-GLI will induce different numbers of neural stem cells in normal development and homeostasis [35,44–48], and also induce different cell fates in the ventral neural tube in response to a morphogenetic gradient of HH ligands [8,9,11,49–51]. On the other hand, genetic and/or epigenetic changes leading to irreversible activation of GLIA, and GLI1 , can drive a variety of malignant states ranging from cancers of the brain, skin, breast, prostate and digestive tract to malignancies of the hematopoietic system (e.g. "
ABSTRACT: Canonical Hedgehog (HH) signaling leads to the regulation of the GLI code: the sum of all positive and negative functions of all GLI proteins. In humans, the three GLI factors encode context-dependent activities with GLI1 being mostly an activator and GLI3 often a repressor. Modulation of GLI activity occurs at multiple levels, including by co-factors and by direct modification of GLI structure. Surprisingly, the GLI proteins, and thus the GLI code, is also regulated by multiple inputs beyond HH signaling. In normal development and homeostasis these include a multitude of signaling pathways that regulate proto-oncogenes, which boost positive GLI function, as well as tumor suppressors, which restrict positive GLI activity. In cancer, the acquisition of oncogenic mutations and the loss of tumor suppressors - the oncogenic load - regulates the GLI code towards progressively more activating states. The fine and reversible balance of GLI activating GLIA and GLI repressing GLIR states is lost in cancer. Here, the acquisition of GLIA levels above a given threshold is predicted to lead to advanced malignant stages. In this review we highlight the concepts of the GLI code, the oncogenic load, the context-dependency of GLI action, and different modes of signaling integration such as that of HH and EGF. Targeting the GLI code directly or indirectly promises therapeutic benefits beyond the direct blockade of individual pathways.Seminars in Cell and Developmental Biology 09/2014; 33(100). DOI:10.1016/j.semcdb.2014.05.003 · 6.27 Impact Factor