Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo

Lai, Ka-Bik; Kaspar, Brian K.; Gage, Fred H.; Schaffer, David V.

doi:10.1038/nn983

Cited by 727 publications

(632 citation statements)

References 50 publications

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“…Administration of glial cell line-derived neurotrophic factor after adult stroke results in less cell death and glial cell linederived neurotrophic factor stimulates subventricular zone neurogenesis and migration of precursor cells toward the site where new neurons are needed (49,50). Sonic hedgehog is a powerful factor that stimulates neural progenitor cell proliferation, migration, and differentiation toward neurons and oligodendrocytes and could thereby contribute to both gray and white matter remodeling (51).…”

Section: Growth-promoting Environmentmentioning

confidence: 99%

Mesenchymal stem cells as a treatment for neonatal ischemic brain damage

Velthoven

Kavelaars²,

Heijnen³

2012

Pediatr Res

134

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Section: Growth-promoting Environmentmentioning

confidence: 99%

Mesenchymal stem cells as a treatment for neonatal ischemic brain damage

Velthoven

Kavelaars²,

Heijnen³

2012

Pediatr Res

134

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“…The cell types that release Shh in the SGZ-GCL neurogenic niche are believed to be astrocytes (Jiao and Chen 2008). Pertaining to adult hippocampal neurogenesis, studies have shown that overexpression of Shh enhances SGZ-NSC proliferation and inhibition of Shh signaling decreases SGZ-NSC proliferation in the postnatal hippocampus (Lai et al 2003). Additional studies suggest that both quiescent NSCs and transit amplifying progenitor cells in the SGZ respond to Shh signaling and contribute to ongoing neurogenesis (Ahn and Joyner 2005;Jiao and Chen 2008).…”

Section: Expression Of Stat3 and Shh Genes Is Enhanced In The Aged Dgmentioning

confidence: 99%

Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus

Shetty

Hattiangady

Shetty

2013

AGE

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Hippocampal neurogenesis, important for memory and mood function, wanes greatly in old age. Studies in rat models have implied that this decrease is not due to loss of neural stem cells (NSCs) in the subgranular zone of the dentate gyrus (DG) but rather due to an increased quiescence of NSCs. Additional studies have suggested that changes in the microenvironment, particularly declines in the concentrations of neurotrophic factors, underlie this change. In this study, we compared the expression of 84 genes that are important for NSC proliferation and neurogenesis between the DG of young (4 months old) and aged (24 months old) Fischer 344 rats, using a quantitative real-time polymerase chain reaction array. Interestingly, the expression of a vast majority of genes that have been reported previously to positively or negatively regulate NSC proliferation was unaltered with aging. Furthermore, most genes important for cell cycle arrest, regulation of cell differentiation, growth factors and cytokine levels, synaptic functions, apoptosis, cell adhesion and cell signaling, and regulation of transcription displayed stable expression in the DG with aging. The exceptions included increased expression of genes important for NSC proliferation and neurogenesis (Stat3 and Shh), DNA damage response and NFkappaB signaling (Cdk5rap3), neuromodulation (Adora1), and decreased expression of a gene important for neuronal differentiation (HeyL). Thus, age-related decrease in hippocampal neurogenesis is not associated with a decline in the expression of selected genes important for NSC proliferation and neurogenesis in the DG.

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“…[14][15][16][17] Shh is a secreted neurodifferentiation factor that binds to a receptor complex, patched (ptc)-smoothened (smo). Binding of Shh to ptc inhibits smo, an inhibitory receptor, 18 stimulating the transduction of the intracellular signaling pathway that leads to the activation of its main downstream transcriptional mediators, [19][20][21][22] that is, the transcription factor Gli1 23,24 ; these proteins are all present within the adult rodent brain.…”

Section: Introductionmentioning

confidence: 99%

“…ShhN protects cultures of fetal dopamine neurons from MPP+ toxicity, 28 and regulates the differentiation and proliferation of neuronal stem cells. 14,15,29 Further, Shh peptide injected directly into the brain of rodents and marmosets has beneficial effects in experimental models of Parkinson's disease. [30][31][32] We have recently demonstrated that adenoviral vectors encoding ShhN, or Gli1 under the control of pancellular viral promoters, have a neuroprotective effect on nigrostriatal dopaminergic neurons in an experimental model of dopamine neurodegeneration induced by 6-OHDA.…”

Section: Introductionmentioning

confidence: 99%

Neuronal expression of the transcription factor Gli1 using the Tα1 α-tubulin promoter is neuroprotective in an experimental model of Parkinson's disease

et al. 2004

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Nigrostriatal neurons degenerate during Parkinson's disease. Experimentally, neurotoxins such as 6-hydroxydopamine (6-OHDA) in rodents, and MPTP in mice and nonhuman primates, are used to model the disease-induced degeneration of midbrain dopaminergic neurons. Glialcell-derived neurotrophic factor (GDNF) is a very powerful neuroprotector of dopaminergic neurons in all species examined. However, recent reports have indicated the possibility that GDNF may, in the long term and if expressed in an unregulated manner, exert untoward effects on midbrain dopaminergic neuronal structure and function. Although GDNF remains a powerful neurotrophin, the search for alternative therapies based on alternative and complementary mechanisms of action to GDNF is warranted. Recently, recombinant adenovirus-derived vectors encoding the differentiation factor Sonic Hedgehog (Shh) and its downstream transcriptional activator (Gli1) were shown to protect dopaminergic neurons in the substantia nigra pars compacta from 6-OHDA-induced neurotoxicity in rats in vivo. A pancellular human CMV (hCMV) promoter was used to drive the expression of both Shh and Gli1. Since Gli1 is a transcription factor and therefore exerts its actions intracellularly, we decided to test whether expression of Gli1 within neurons would be effective for neuroprotection. We demonstrate that neuronal-specific expression of Gli1 using the neuron-specific Ta1 a-tubulin (Ta1) promoter was neuroprotective, and its efficiency was comparable to the pancellular strong viral hCMV promoter. These results suggest that expression of the transcription factor Gli1 solely within neurons is neuroprotective for dopaminergic neurons in vivo and, furthermore, that neuronal-specific promoters are effective within the context of adenovirus-mediated gene therapy-induced neuroprotection of dopaminergic midbrain neurons. Since cell-type specific promoters are known to be weaker than the viral hCMV promoter, our data demonstrate that neuronal-specific expression of transcription factors is an effective, specific, and sufficient targeted approach for neurological gene therapy applications, potentially minimizing side effects due to unrestricted promiscuous gene expression within target tissues.

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Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo

Cited by 727 publications

References 50 publications

Mesenchymal stem cells as a treatment for neonatal ischemic brain damage

Mesenchymal stem cells as a treatment for neonatal ischemic brain damage

Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus

Neuronal expression of the transcription factor Gli1 using the Tα1 α-tubulin promoter is neuroprotective in an experimental model of Parkinson's disease

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