Thyroid Hormone-Otx2 Signaling Is Required for Embryonic Ventral Midbrain Neural Stem Cells Differentiated into Dopamine Neurons

Chen, Chunhai; Ma, Qinglong; Chen, Xiaowei; Zhong, Min; Deng, Ping; Zhu, Gang; Zhang, Yanwen; Zhang, Lei; Yang, Zhiqi; Guo, Lei; Wang, Liting; Yu, Zhengping; Zhou, Zhou

doi:10.1089/scd.2014.0489

Cited by 27 publications

(19 citation statements)

References 70 publications

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“…Three independent experiments were performed for every condition. The EdU + were expressed as a percentage of total cells determined by Hoechst33342 staining [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

TLR4 Activation Promotes Bone Marrow MSC Proliferation and Osteogenic Differentiation via Wnt3a and Wnt5a Signaling

Wang

Jin

et al. 2016

PLoS ONE

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Mesenchymal stem cells (MSCs) from adult bone marrow maintain their self-renewal ability and the ability to differentiate into osteoblast. Thus, adult bone marrow MSCs play a key role in the regeneration of bone tissue. Previous studies indicated that TLR4 is expressed in MSCs and is critical in regulating the fate decision of MSCs. However, the exact functional role and underlying mechanisms of how TLR4 regulate bone marrow MSC proliferation and differentiation are unclear. Here, we found that activated TLR4 by its ligand LPS promoted the proliferation and osteogenic differentiation of MSCs in vitro. TLR4 activation by LPS also increased cytokine IL-6 and IL-1β production in MSCs. In addition, LPS treatment has no effect on inducing cell death of MSCs. Deletion of TLR4 expression in MSCs completely eliminated the effects of LPS on MSC proliferation, osteogenic differentiation and cytokine production. We also found that the mRNA and protein expression of Wnt3a and Wnt5a, two important factors in regulating MSC fate decision, was upregulated in a TLR4-dependent manner. Silencing Wnt3a with specific siRNA remarkably inhibited TLR4-induced MSC proliferation, while Wnt5a specific siRNA treatment significantly antagonized TLR4-induced MSC osteogenic differentiation. These results together suggested that TLR4 regulates bone marrow MSC proliferation and osteogenic differentiation through Wnt3a and Wnt5a signaling. These finding provide new data to understand the role and the molecular mechanisms of TLR4 in regulating bone marrow MSC functions. These data also provide new insight in developing new therapy in bone regeneration using MSCs by modulating TLR4 and Wnt signaling activity.

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“…Three independent experiments were performed for every condition. The EdU + were expressed as a percentage of total cells determined by Hoechst33342 staining [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

TLR4 Activation Promotes Bone Marrow MSC Proliferation and Osteogenic Differentiation via Wnt3a and Wnt5a Signaling

Wang

Jin

et al. 2016

PLoS ONE

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“…Transthyretin, the protein transporting TH into the cerebrospinal fluid, is synthesized by the choroid plexus (Richardson et al, 2015). Yet, more importantly, Otx2 production can be regulated by THr activation as shown in midbrain stem cells (Chen et al, 2015). Whether TH controls Otx2 synthesis in the choroid plexus remains unknown.…”

Section: Cp Regulation Through Thyroid Hormones: Potential Linksmentioning

confidence: 99%

“…Whether TH controls Otx2 synthesis in the choroid plexus remains unknown. But given its role in midbrain (Chen et al, 2015), it is possible that TH acts as a permissive signal to set the onset of the CP by enhancing Otx2 production and PV maturation (Figure 2).…”

Section: Cp Regulation Through Thyroid Hormones: Potential Linksmentioning

confidence: 99%

Critical Period Regulation by Thyroid Hormones: Potential Mechanisms and Sex-Specific Aspects

Batista

Hensch

2019

Front. Mol. Neurosci.

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Adequate perinatal levels of thyroid hormones (THs) are required for normal brain function and development. Studies in non-mammalian species suggest that TH might be involved in the regulation of critical periods (CPs) of heightened plasticity. Yet, it is largely unknown what mechanisms controlling such CPs might be under TH regulation. Here, we briefly review the influence of TH in early life across evolution. We discuss possible links between TH and known circuit and/or molecular mechanisms determining the timing of CPs of heightened brain plasticity. We focus on the role of parvalbumin-positive (PV) interneurons since their maturation defines CP onset and closure. Specifically, abnormal PV circuits are associated with low perinatal levels of TH, possibly because thyroid hypofunction may increase oxidative stress and/or dysregulate Otx2-mediated maturation of neuroprotective perineuronal nets. In addition, the level of cholinergic transmission is important for CP plasticity. Potentially, TH levels could affect gain changes in cholinergic transmission that can alter brain development. We believe that understanding how TH impacts CPs of circuit refinement will shed light onto the principles underlying normal developmental trajectories. Given that the thyroid gland expresses estrogen and androgen receptors, its activity can potentially be regulated differently between the sexes, contributing to sexually dimorphic behaviors.

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“…In the present study, we also found transcript upregulation of Otx2, encoding orthodenticle homeobox 2 (OTX2), an essential morphogen for embryonic head formation (Sugiyama et al, 2009), in the dentate gyrus after cessation of developmental hypothyroidism. Expression of this gene is thyroid hormone-dependent (Chen et al, 2015), and OTX2 plays a role for promoting maturation of PVALB + cells in the visual cortex (Sugiyama et al, 2009). In the present study, transcript upregulation of Otx2 in PTU-alone group may be the compensatory response to facilitate maturation of PVALB + interneurons that were reduced in number due to sustained oxidative stress responses induced by developmental hypothyroidism.…”

Section: Discussionmentioning

confidence: 49%

Ameliorating effect of postweaning exposure to antioxidant on disruption of hippocampal neurogenesis induced by developmental hypothyroidism in rats

et al. 2019

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Developmental hypothyroidism as a model of autism spectrum disorders disrupts hippocampal neurogenesis through the adult stage. The present study investigated the ameliorating effect of postweaning exposure to antioxidant on the hypothyroidism-induced disruptive neurogenesis. Mated female Sprague-Dawley rats were treated with 0 or 10 ppm 6-propyl-2-thiouracil (PTU) as an anti-thyroid agent in drinking water from gestational day 6 to postnatal day (PND) 21 on weaning. PTU-exposed male offspring were fed either basal diet, diet containing α-glycosyl isoquercitrin (AGIQ) at 5,000 ppm or α-lipoic acid (ALA) at 1,000 ppm as an antioxidant from PND 21 to PND 77. PTU-exposure decreased DCX + and NeuN + granule cell lineage subpopulations, synaptic plasticity-related FOS + granule cells, and hilar PVALB + and GAD67 + GABAergic interneurons, increased hilar SST + and CALB2 + interneurons, and upregulated Gria3, Otx2, and antioxidant enzyme genes in the dentate gyrus on PND 77. These results suggest disruption of neurogenesis remained in relation with increase of oxidative stress and compensatory responses to the disruption at the adult stage. AGIQ recovered expression of some antioxidant enzyme genes and was effective for restoration of NeuN + postmitotic granule cells and PVALB + and SST + interneurons. In contrast, ALA was effective for restoration of all interneuron subpopulations, as well as postmitotic granule cells, and upregulated Grin2a that may play a role for the restoration. Both antioxidants recovered expression of Otx2 and AGIQ-alone recovered Gria3, suggesting a reversal of disruptive neurogenesis by compensatory responses. Thus, postweaning antioxidant exposure may be effective for ameliorating developmental hypothyroidism-induced disruptive neurogenesis by restoring the function of regulatory system.

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Thyroid Hormone-Otx2 Signaling Is Required for Embryonic Ventral Midbrain Neural Stem Cells Differentiated into Dopamine Neurons

Cited by 27 publications

References 70 publications

TLR4 Activation Promotes Bone Marrow MSC Proliferation and Osteogenic Differentiation via Wnt3a and Wnt5a Signaling

TLR4 Activation Promotes Bone Marrow MSC Proliferation and Osteogenic Differentiation via Wnt3a and Wnt5a Signaling

Critical Period Regulation by Thyroid Hormones: Potential Mechanisms and Sex-Specific Aspects

Ameliorating effect of postweaning exposure to antioxidant on disruption of hippocampal neurogenesis induced by developmental hypothyroidism in rats

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