Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenotypes in the Nurr1-overexpressing neural stem cell

Kim, Tae Eun; Lee, Hack Sup; Lee, Yong Beom; Hong, Samin; Lee, Young Seek; Ichinose, Hiroshi; Kim, Seung Up; Lee, Myung Ae

doi:10.1016/s0006-291x(03)00879-9

Cited by 77 publications

(40 citation statements)

References 33 publications

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“…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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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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“…It is reasonable, however, to conclude that Shh may play an important role in the early patterning of uncommitted stem cells to adopt dopaminergic cell fate but may have inhibitory effects on TH expression when expressed during the terminal stages of differentiation. A previous study with the immortalized neural stem cells has shown that ShhN increases TH expression only in combination with FGF-8 and Nurr-1 [20]. It will be of interest to see whether the mild inhibitory function of ShhN alone is converted into a stimulatory one by FGF-8 and Nurr-1.…”

Section: Determination Of Tyrosine Hydroxylase Expressionmentioning

confidence: 96%

“…In embryonic stem cells, Shh plus FGF8 increases the number of THpositive cells [20]. In adult hippocampal progenitor cells, constitutive expression of ShhN increases TH expression prior to differentiation but decreases it in terminally differentiating neurons [10].…”

Section: Determination Of Tyrosine Hydroxylase Expressionmentioning

confidence: 99%

Differential regulation of tyrosine hydroxylase expression by sonic hedgehog

Kwon

Park²,

Choi³

et al. 2006

NeuroReport

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Sonic hedgehog functions to induce £oor plate in early stages, and spinal motor neurons and midbrain dopaminergic neurons in later stages of development. Here, we investigated the e¡ects of sonic hedgehog on tyrosine hydroxylase expression in three cell lines that correspond to di¡erent stages of neural development. Sonic hedgehog increased the tyrosine hydroxylase gene expression in pluripotent P19 cells but repressed it in tyrosine hydroxylaseproducing PC12 cells. Promoter analysis in mouse neural stem cells indicated that the N-terminal of sonic hedgehog repressed both the basal and cAMP-dependent protein kinase A-mediated tyrosine hydroxylase activity.These results suggest that the N-terminal of sonic hedgehog increases tyrosine hydroxylase gene expression in cells to acquire dopaminergic phenotypes, but decreases expression in late born neurons by antagonizing the protein kinase A cAMP-responsive element binding protein pathway. NeuroReport 17:693^698

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“…These active growth factors include interleukin-1beta, glial cell line-derived neurotrophic factor (GDNF), neurturin, transforming growth factorbeta3, dibutyryl-cyclic AMP [7,8], sonic hedgehog [9-11], fibroblast growth factor-8 (FGF8) [11], and brain-derived neurotrophic factor (BDNF) [12][13][14][15][16], and, the signaling transductions involving Bcl-XL [17], Lmx1b/Wnt [18], developmental transcription factors ASCL1, NURR1, and LMX1A [19]. The third approach is to supply spherical neural masses as a physical method for producing the high yield of dopamine neurons [20,21].…”

mentioning

confidence: 99%

Nonviral Reprogramming Genes Accelerate Formation of Neurons from Murine Embryonic Brain Cells: Synergistic Effect of Brain Derived Neurotrophic Factor Gene Therapy

Liu¹

2016

Transl Med (sunnyvale)

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Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenotypes in the Nurr1-overexpressing neural stem cell

Cited by 77 publications

References 33 publications

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

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

Differential regulation of tyrosine hydroxylase expression by sonic hedgehog

Nonviral Reprogramming Genes Accelerate Formation of Neurons from Murine Embryonic Brain Cells: Synergistic Effect of Brain Derived Neurotrophic Factor Gene Therapy

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