Palma V, Lim DA, Dahmane N, Sanchez P, Brionne TC, Herzberg CD et al.. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development 132: 335-344

University of California, San Francisco, San Francisco, California, United States
Development (Impact Factor: 6.46). 02/2005; 132(2):335-44. DOI: 10.1242/dev.01567
Source: PubMed


Sonic hedgehog (Shh) signaling controls many aspects of ontogeny, orchestrating congruent growth and patterning. During brain development, Shh regulates early ventral patterning while later on it is critical for the regulation of precursor proliferation in the dorsal brain, namely in the neocortex, tectum and cerebellum. We have recently shown that Shh also controls the behavior of cells with stem cell properties in the mouse embryonic neocortex, and additional studies have implicated it in the control of cell proliferation in the adult ventral forebrain and in the hippocampus. However, it remains unclear whether it regulates adult stem cell lineages in an equivalent manner. Similarly, it is not known which cells respond to Shh signaling in stem cell niches. Here we demonstrate that Shh is required for cell proliferation in the mouse forebrain's subventricular zone (SVZ) stem cell niche and for the production of new olfactory interneurons in vivo. We identify two populations of Gli1+ Shh signaling responding cells: GFAP+ SVZ stem cells and GFAP- precursors. Consistently, we show that Shh regulates the self-renewal of neurosphere-forming stem cells and that it modulates proliferation of SVZ lineages by acting as a mitogen in cooperation with epidermal growth factor (EGF). Together, our data demonstrate a critical and conserved role of Shh signaling in the regulation of stem cell lineages in the adult mammalian brain, highlight the subventricular stem cell astrocytes and their more abundant derived precursors as in vivo targets of Shh signaling, and demonstrate the requirement for Shh signaling in postnatal and adult neurogenesis.

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Available from: Alan Carleton, Oct 09, 2015
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    • "Shh plays a role in the early development of OSNs and has been implicated in initial OSN axon branching and innervation of the olfactory bulb (Gong et al., 2009). At later stages, Shh promotes proliferation of olfactory interneuron progenitor populations in the SVZ and also functions as a chemoattractant, promoting the migration of neuroblasts along the RMS (Palma et al., 2005; Hor and Tang, 2010). Thus, Shh has the potential to regulate multiple, complementary cellular constituents of the glomerular circuit. "
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    ABSTRACT: The olfactory system relies on precise circuitry connecting olfactory sensory neurons (OSNs) and appropriate relay and processing neurons of the olfactory bulb (OB). In mammals, the exact correspondence between specific olfactory receptor types and individual glomeruli enables a spatially precise map of glomerular activation that corresponds to distinct odors. However, the mechanisms that govern the establishment and maintenance of the glomerular circuitry are largely unknown. Here we show that high levels of Sonic Hedgehog (Shh) signaling at multiple sites enable refinement and maintenance of olfactory glomerular circuitry. Mice expressing a mutant version of Shh (Shh(Ala/Ala) ), with impaired binding to proteoglycan co-receptors, exhibit disproportionately small olfactory bulbs containing fewer glomeruli. Notably, in mutant animals the correspondence between individual glomeruli and specific olfactory receptors is lost, as olfactory sensory neurons expressing different olfactory receptors converge on the same glomeruli. These deficits arise at late stages in post-natal development and continue into adulthood, indicating impaired pruning of erroneous connections within the olfactory bulb. In addition, mature Shh(Ala/Ala) mice exhibit decreased proliferation in the subventricular zone (SVZ), with particular reduction in neurogenesis of calbindin-expressing periglomerular cells. Thus, Shh interactions with proteoglycan co-receptors function at multiple locations to regulate neurogenesis and precise olfactory connectivity, thereby promoting functional neuronal circuitry. © 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014.
    Developmental Neurobiology 12/2014; 74(12). DOI:10.1002/dneu.22202 · 3.37 Impact Factor
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    • "Interestingly, initial evidence for non-HH signaling regulating the GLI code came from studies with frog embryos where GLI2 was found to act in the FGF-Brachyury loop in the early mesoderm [87]. In a separate study, the growth of mouse brain neurospheres was found to be dependent on both EGF and Sonic HH (SHH) signaling but only after decreasing their levels [46,47]. This synergism between EGF and SHH [47], together with the regulation of GLI2 by FGF [87], and the regulation of GLI1 by RAS-MEK-AKT [65] opened a new chapter on the regulation of the GLI code, in this case by non-HH signals. "
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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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    • "Promoting endogenous repair is particularly attractive in mild–moderate forms of TBI, for which stem cell therapy may not be required or appropriate. Sonic hedgehog (Shh) is a critical signaling pathway that maintains the neural stem cells in the adult SVZ (Palma et al., 2005; Balordi and Fishell, 2007; Petrova et al., 2013). Shh protein expression is maintained in the normal adult telencephalon and increases after cortical or white matter damage (Machold et al., 2003; Ferent et al., 2013; Sirko et al., 2013). "
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    ABSTRACT: The regenerative capacity of the central nervous system must be optimized to promote repair following traumatic brain injury (TBI) and may differ with the site and form of damage. Sonic hedgehog (Shh) maintains neural stem cells and promotes oligodendrogenesis. We examined whether Shh signaling contributes to neuroblast (doublecortin) or oligodendrocyte progenitor (neural/glial antigen 2 [NG2]) responses in two distinct TBI models. Shh-responsive cells were heritably labeled in vivo using Gli1-CreER(T2);R26-YFP bitransgenic mice with tamoxifen administration on Days 2 and 3 post-TBI. Injury to the cerebral cortex was produced with mild controlled cortical impact. Yellow fluorescent protein (YFP) cells decreased in cortical lesions. Total YFP cells increased in the subventricular zone (SVZ), indicating Shh pathway activation in SVZ cells, including doublecortin-labeled neuroblasts. The alternate TBI model produced traumatic axonal injury in the corpus callosum. YFP cells decreased within the SVZ and were rarely double labeled as NG2 progenitors. NG2 progenitors increased in the cortex, with a similar pattern in the corpus callosum. To further test the potential of NG2 progenitors to respond through Shh signaling, Smoothened agonist was microinjected into the corpus callosum to activate Shh signaling. YFP cells and NG2 progenitors increased in the SVZ but were not double labeled. This result indicates that either direct Smoothened activation in NG2 progenitors does not signal through Gli1 or that Smoothened agonist acts indirectly to increase NG2 progenitors. Therefore, in all conditions, neuroblasts exhibited differential Shh pathway utilization compared with oligodendrocyte progenitors. Notably, cortical versus white matter damage from TBI produced opposite responses of Shh-activated cells within the SVZ.
    ASN Neuro 07/2014; 6(5). DOI:10.1177/1759091414551782 · 4.02 Impact Factor
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