Differential regulation of tyrosine hydroxylase expression by sonic hedgehog

Kwon, Ii Sun; Park, Rae Hee; Choi, Jung Mi; Kim, Seung Up; Lee, Young Don; Suh‐Kim, Haeyoung

doi:10.1097/01.wnr.0000209043.66482.0b

Cited by 3 publications

(7 citation statements)

References 21 publications

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“…Based on previous reports and our microarray results, we hypothesized that manipulation of these pathways at the appropriate developmental stage would affect dopaminergic neuronal differentiation process using our protocol. SHH is a member of the hedgehog family of signaling molecules, which are implicated in numerous developmental events, including growth and patterning of the neural tube [24][25][26][27][28]. SHH is a secreted signaling protein that binds to the receptor smoothened (SMO) and activates signal transduction pathway [24] that promotes differentiation of NSC or neural precursors into immature dopaminergic neurons [12,24,25].…”

Section: Functional Validations Of Microarray Resultsmentioning

confidence: 99%

Genome Wide Profiling of Dopaminergic Neurons Derived from Human Embryonic and Induced Pluripotent Stem Cells

Momčilović

Liu

Swistowski

et al. 2014

Stem Cells and Development

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Recent advances in human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) biology enable generation of dopaminergic neurons for potential therapy and drug screening. However, our current understanding of molecular and cellular signaling that controls human dopaminergic development and function is limited. Here, we report on a whole genome analysis of gene expression during dopaminergic differentiation of human ESC/iPSC using Illumina bead microarrays. We generated a transcriptome data set containing the expression levels of 28,688 unique transcripts by profiling five lines (three ESC and two iPSC lines) at four stages of differentiation: (1) undifferentiated ESC/iPSC, (2) neural stem cells, (3) dopaminergic precursors, and (4) dopaminergic neurons. This data set provides comprehensive information about genes expressed at each stage of differentiation. Our data indicate that distinct pathways are activated during neural and dopaminergic neuronal differentiation. For example, WNT, sonic hedgehog (SHH), and cAMP signaling pathways were found over-represented in dopaminergic populations by gene enrichment and pathway analysis, and their role was confirmed by perturbation analyses using RNAi (small interfering RNA of SHH and WNT) or small molecule [dibutyryl cyclic AMP (dcAMP)]. In summary, whole genome profiling of dopaminergic differentiation enables systematic analysis of genes/pathways, networks, and cellular/molecular processes that control cell fate decisions. Such analyses will serve as the foundation for better understanding of dopaminergic development, function, and development of future stem cell-based therapies. IntroductionD opaminergic neurons form a neurotransmitter system that originates in the substantia nigra pars compacta, ventral tegmental area, and hypothalamus. Several diseases of the central nervous system, such as Parkinson's disease (PD), schizophrenia, and attention deficit hyperactivity disorder, are associated with dysfunctions of the dopamine system. Knowledge of the molecular mechanisms that regulate human dopaminergic development and function may provide better understanding of the causes for these diseases and offer clues for new treatments. The development and function of human dopaminergic neurons remain relatively uncharacterized at the molecular level compared to rodents. Therefore, studies of the underlying molecular mechanisms of the above-mentioned diseases have been largely hampered by the limited availability of human cells at the appropriate stages of dopaminergic development.The recent advances in human pluripotent stem cell (PSC) biology enable reprogramming of human adult somatic cells from healthy subjects and patients to induced pluripotent stem cells (iPSC) [1,2]. The reprogramming technology and derivation of iPSC followed by their differentiation allow the generation of sufficient numbers of human dopaminergic neurons at different stages of development for both in vitro and in vivo studies. Several groups have reported on the generation of functional ...

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Section: Functional Validations Of Microarray Resultsmentioning

confidence: 99%

Genome Wide Profiling of Dopaminergic Neurons Derived from Human Embryonic and Induced Pluripotent Stem Cells

Momčilović

Liu

Swistowski

et al. 2014

Stem Cells and Development

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“…Hedgehog (Hh) signaling is generally lower in adults than in embryos but was recently suggested to play an important role in the control of embryonic and adult stem cell growth [1]. Among the members of the mammalian hedgehog proteins (Sonic, Indian, Desert), sonic hedgehog (Shh) has received the most attention and acts on the target cells to increase the transcription of several genes, including members of Wnt , Notch , and several growth factors such as fibroblast growth factor, transforming growth factor β families, and the receptor Patched (Ptc), which releases the Ptc‐mediated repression of Smoothened (Smo) [2, –4]. It is known that the end point of the Shh signal pathway, representing the nuclear component of the pathway, is the zinc‐finger transcription factor Gli (Ci [Cubitus interruptus] in Drosophila species) [5].…”

Section: Introductionmentioning

confidence: 99%

Sonic Hedgehog Stimulates Mouse Embryonic Stem Cell Proliferation by Cooperation of Ca2+/Protein Kinase C and Epidermal Growth Factor Receptor As Well as Gli1 Activation

2007

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“…As studies have shown that SHH antagonistically regulates cAMP dependent PKA in TH expressing cells (Kwon et al, ), we measured the cAMP levels in SHED and DPSCs at all 3 day points of induction. As represented in Figure , the cAMP levels in SHED (which express TH in their naïve state) was significantly reduced in the presence of the morphogen SHH on day 3 ( P < 0.05) and this reduced level persisted on days 6 and 9 ( P < 0.05).…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we have shown that higher expression of mature neuronal markers and dopaminergic markers did not preferentially predispose SHED for greater dopaminergic differentiation capacity than DPSCs. In fact, an earlier study showed that sonic hedgehog repressed TH expression in cells already expressing the marker spontaneously in naïve state (Kwon et al, ). The expression of the dopaminergic transcription factors En1, Nurr1, and Pitx3 in naïve SHED and DPSCs were found to be localized in the cytosol unlike in positive control cells, in turn suggesting their inability to functionally secrete dopamine.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study, we have reported the capability of DPSCs to differentiate to functional dopaminergic neurons under the influence of this mid‐brain cue (SHH) along with fibroblast growth factor 8 and basic fibroblast growth factor (Kanafi et al, ). On the other hand, SHH has been shown to have an opposing effect on cells expressing TH in the naïve state through the down‐regulation of cAMP dependent PKA (Kwon et al, ). SHED has been reported to spontaneously express end‐neuronal markers along with TH in their naïve state, so just the presence of mid‐brain cues may not dictate dopaminergic fate commitment in SHED.…”

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confidence: 99%

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Differential Neuronal Plasticity of Dental Pulp Stem Cells From Exfoliated Deciduous and Permanent Teeth Towards Dopaminergic Neurons

Majumdar

Kanafi

Bhonde

et al. 2016

Journal Cellular Physiology

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Based on early occurrence in chronological age, stem-cells from human exfoliated deciduous teeth (SHED) has been reported to possess better differentiation-potential toward certain cell-lineage in comparison to stem-cells from adult teeth (DPSCs). Whether this same property between them extends for the yield of functional central nervous system neurons is still not evaluated. Hence, we aim to assess the neuronal plasticity of SHED in comparison to DPSCs toward dopaminergic-neurons and further, if the difference is reflected in a differential expression of sonic-hedgehog (SHH)-receptors and basal-expressions of tyrosine-hydroxylase [TH; through cAMP levels]. Human SHED and DPSCs were exposed to midbrain-cues [SHH, fibroblast growth-factor8, and basic fibroblast growth-factor], and their molecular, immunophenotypical, and functional characterization was performed at different time-points of induction. Though SHED and DPSCs spontaneously expressed early-neuronal and neural-crest marker in their naïve state, only SHED expressed a high basal-expression of TH. The upregulation of dopaminergic transcription-factors Nurr1, Engrailed1, and Pitx3 was more pronounced in DPSCs. The yield of TH-expressing cells decreased from 49.8% to 32.16% in SHED while it increased from 8.09% to 77.47% in DPSCs. Dopamine release and intracellular-Ca(2+) influx upon stimulation (KCl and ATP) was higher in induced DPSCs. Significantly lower-expression of SHH-receptors was noted in naïve SHED than DPSCs, which may explain the differential neuronal plasticity. In addition, unlike DPSCs, SHED showed a down-regulation of cyclic adenosine-monophosphate (cAMP) upon exposure to SHH; possibly another contributor to the lesser differentiation-potential. Our data clearly demonstrates for the first time that DPSCs possess superior neuronal plasticity toward dopaminergic-neurons than SHED; influenced by higher SHH-receptor and lower basal TH expression. J. Cell. Physiol. 231: 2048-2063, 2016. © 2016 Wiley Periodicals, Inc.

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Differential regulation of tyrosine hydroxylase expression by sonic hedgehog

Cited by 3 publications

References 21 publications

Genome Wide Profiling of Dopaminergic Neurons Derived from Human Embryonic and Induced Pluripotent Stem Cells

Genome Wide Profiling of Dopaminergic Neurons Derived from Human Embryonic and Induced Pluripotent Stem Cells

Sonic Hedgehog Stimulates Mouse Embryonic Stem Cell Proliferation by Cooperation of Ca2+/Protein Kinase C and Epidermal Growth Factor Receptor As Well as Gli1 Activation

Differential Neuronal Plasticity of Dental Pulp Stem Cells From Exfoliated Deciduous and Permanent Teeth Towards Dopaminergic Neurons

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