Lai, K., Kaspar, B.K., Gage, F.H. & Schaffer, D.V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat. Neurosci. 6, 21-27

Department of Chemical Engineering and The Helen Wills Neuroscience Institute, 201 Gilman Hall, University of California, Berkeley, California 94720-1462, USA.
Nature Neuroscience (Impact Factor: 16.1). 02/2003; 6(1):21-7. DOI: 10.1038/nn983
Source: PubMed


Neural stem cells exist in the developing and adult nervous systems of all mammals, but the basic mechanisms that control their behavior are not yet well understood. Here, we investigated the role of Sonic hedgehog (Shh), a factor vital for neural development, in regulating adult hippocampal neural stem cells. We found high expression of the Shh receptor Patched in both the adult rat hippocampus and neural progenitor cells isolated from this region. In addition, Shh elicited a strong, dose-dependent proliferative response in progenitors in vitro. Furthermore, adeno-associated viral vector delivery of shh cDNA to the hippocampus elicited a 3.3-fold increase in cell proliferation. Finally, the pharmacological inhibitor of Shh signaling cyclopamine reduced hippocampal neural progenitor proliferation in vivo. This work identifies Shh as a regulator of adult hippocampal neural stem cells.

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Available from: Brian Kaspar, Oct 02, 2014
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    • "Exogenous Shh protein has also been shown to increase the production of multipotent, self-renewing neurospheres cultured from adult stem cells of the V-SVZ or SGZ, suggesting that signaling through this pathway affects stem cell proliferation, the balance between self-renewal and differentiation, or both [11] [63]. In contrast to the localization of Shh transcript and subsequent analyses using knock-in mouse alleles to label cell bodies, Shh protein has been detected in the dentate gyrus, cerebrospinal fluid, and the neuropil surrounding the ventral V-SVZ [63] [64]. However, the mechanisms through which Shh protein is secreted and reaches these regions remain to be elucidated. "
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    ABSTRACT: Sonic hedgehog (Shh) is a pleiotropic factor in the developing central nervous system (CNS), driving proliferation, specification, and axonal targeting in multiple sites within the forebrain, hindbrain, and spinal cord. Studies in embryonic CNS have shown how gradients of this morphogen are translated by neuroepithelial precursors to determine the types of neurons and glial cells they produce 0005 and 0010. Shh also has a well-characterized role as a mitogen for specific progenitor cell types in neural development 0015 and 0020. As we begin to appreciate that Shh continues to act in the adult brain, a central question is what functional role this ligand plays when major morphogenetic and proliferative processes are no longer in operation. A second fundamental question is whether similar signaling mechanisms operate in embryonic and adult CNS. In the two major germinal zones of the adult brain, Shh signaling modulates the self-renewal and specification of astrocyte-like primary progenitors, frequently referred to as neural stem cells (NSCs). It also may regulate the response of the mature brain to injury, as Shh signaling has been variously proposed to enhance or inhibit the development of a reactive astrocyte phenotype. The identity of cells producing the Shh ligand, and the conditions that trigger its release, are also areas of growing interest; both germinal zones in the adult brain contain Shh-responsive cells but do not autonomously produce this ligand. Here, we review recent findings revealing the function of this fascinating pathway in the postnatal and adult brain, and highlight ongoing areas of investigation into its actions long past the time when it shapes the developing brain.
    Seminars in Cell and Developmental Biology 09/2014; 33. DOI:10.1016/j.semcdb.2014.05.008 · 6.27 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 [52], 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. "
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    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
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    • "In Drosophila these are the Ci proteins and the mammalian homologues of these are the Gli proteins (1). This downstream signaling initiates the entry of cells into the cell cycle (14) in order to maintain the self-renewal of stem cells in various tissues (15), inhibit apoptosis (16), modulate tissue polarity (17) and regulate the differentiation of tissue stem cells (18). Evidence has suggested that the Hh signaling pathway is prominent in cancer stem cells (19). "
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    ABSTRACT: The Hedgehog (Hh) signaling pathway regulates a variety of tumor-related diseases, including leukemia. The present study aimed to determine whether there was an interaction between the Hh signaling pathway and transforming growth factor (TGF)-β in the KG-1 cell line. KG-1 cells were treated with TGF-β, tumor necrosis factor (TNF)-α and specific inhibitor of smad3 (SIS3). The expression level of Gli family zinc finger 2 (Gli2) was detected by quantitative polymerase chain reaction (qPCR) and western blot analyses. The results revealed that TGF-β significantly decreased the expression level of Gli2 in KG-1 cells, and that TNF-α and TGF-β together further reduced Gli2 expression in KG-1 cells. SIS3 inhibited the effect of TGF-β. These results suggest that Gli2 expression in KG-1 cells is suppressed by TGF-β in a Smad3-dependent manner, TNF-α can enhance the effect of TGF-β on Gli2 expression and that this occurs independently of Hh receptor signaling.
    Experimental and therapeutic medicine 08/2014; 8(2):676-680. DOI:10.3892/etm.2014.1743 · 1.27 Impact Factor
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