Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci

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: 14.98). 02/2003; 6(1):21-7. DOI: 10.1038/nn983
Source: PubMed

ABSTRACT 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 · 5.97 Impact Factor
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    • "Pharmacological inhibition of SHH signaling with cyclopamine also reduced the cell proliferation in the DG (Lai et al., 2003). Conversely, elevated hedgehog signaling produced increased cell proliferation in the DG, further confirming the mitogenic effects of SHH in vivo (Lai et al., 2003; Machold et al., 2003; Han et al., 2008). Interestingly, it appears that the SHH signaling required for DG proliferation is mediated via primary cilia. "
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    ABSTRACT: Granule neurons in the hippocampal dentate gyrus (DG) receive their primary inputs from the cortex and are known to be continuously generated throughout adult life. Ongoing integration of newborn neurons into the existing hippocampal neural circuitry provides enhanced neuroplasticity, which plays a crucial role in learning and memory; deficits in this process have been associated with cognitive decline under neuropathological conditions. In this Primer, we summarize the developmental principles that regulate the process of DG neurogenesis and discuss recent advances in harnessing these developmental cues to generate DG granule neurons from human pluripotent stem cells.
    Development 06/2014; 141(12):2366-75. DOI:10.1242/dev.096776 · 6.27 Impact Factor
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    • " factor beta - 1 is a heparin binding molecule ( McCaffrey et al . , 1992 ) that inhibit cell proliferation in the SVZ ( Wachs et al . , 2006 ) . In the other hand , Sonic hedgehog and heparin - binding epidermal growth factor are heparin binding molecules ( Chang et al . , 2011 ; Jin et al . , 2002 ) that stimulate cell proliferation in the SVZ ( Lai et al . , 2003 ; Jin et al . , 2002 ) ."
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    ABSTRACT: Fractones are extracellular matrix structures that display a fractal ultrastructure and that are visualized as puncta after immunolabeling for laminin or heparan sulfate proteoglycans. In the adult brain, fractones are found throughout the subventricular zone (SVZ). The role of fractones is just emerging. We have recently shown that fractones sequester fibroblast growth factor-2 and bone morphogenetic protein-7 from the brain ventricles to regulate cell proliferation in the SVZ of the lateral ventricle, the primary neural stem cell niche and neurogenic zone in adulthood. Here, we have examined in vivo the effect of bone morphogenetic protein-4 (BMP-4) on cell proliferation in the SVZ and we have determined whether BMP-4 interacts with fractones to promote this effect. To examine BMP-4 effect on cell proliferation, BMP-4 was intracerebroventricularly injected, and bromodeoxyuridine immunolabeling was performed on frozen sections of the adult mouse brain. To identify the location of BMP-4 binding, biotinylated-BMP-4 was injected, and its binding localized post-mortem with streptavidin, Texas red conjugate. Injection of heparitinase-1 was used to desulfate fractones and determine whether the binding and the effect of BMP-4 on cell proliferation are heparan sulfate-dependent. BMP-4 inhibited cell proliferation in the SVZ neurogenic zone. Biotinylated-BMP-4 bound to fractones and some adjacent blood vessels. Co--injection of heparitinase-1 and biotinylated-BMP-4 resulted in the absence of signal for biotinylated-BMP-4, indicating that the binding was heparan sulfate dependent. Moreover, preventing the binding of BMP-4 to fractones by heparitinase-1 reinforced the inhibitory effect of BMP-4 on cell proliferation in the SVZ. These results show that BMP-4 inhibits cell proliferation in the SVZ neurogenic zone and that the binding of BMP-4 to fractone-associated heparan sulfates moderates this inhibitory effect. Together with our previous results, these data support the view that fractones capture growth factors and modulate their activity in the neural tissues lining the ventricles.
    Journal of Chemical Neuroanatomy 05/2014; DOI:10.1016/j.jchemneu.2014.03.005 · 2.52 Impact Factor
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