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The Dietary Flavonoid, Luteolin, Negatively Affects Neuronal Differentiation.

ABSTRACT: Luteolin, a polyphenolic plant flavonoid, has been attributed with numerous beneficial properties like anti-cancer, antioxidant, and anti-inflammatory action. Luteolin has been reported earlier to be neuroprotective in models of spinal cord injury and traumatic brain injury and also induces neurite outgrowth in PC12 cells. However, the effect of luteolin on early differentiation, which might be important for its beneficial effects, is unknown. In this report, we show that luteolin negatively affects early differentiation of embryonic stem cells, hampering the formation of embryoid bodies. At later stages of differentiation, luteolin specifically inhibits neuronal differentiation, where the expression of early neuronal markers is suppressed, whereas luteolin treatment does not inhibit expression of meso- and endodermal markers. Further, in a developing zebrafish model, luteolin treatment leads to fewer numbers of mitotic cells in the brain. These specific effects of luteolin on neuronal differentiation could possibly be due to its ability to inhibit the lysine acetyltransferase, p300, since the structurally closely related p300 non-inhibitor flavonoid, apigenin, does not inhibit neuronal differentiation. These results show that luteolin perturbs neuronal differentiation of embryonic stem cells.

SUBMITTER: Swaminathan A

PROVIDER: S-EPMC6418693 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Dietary Flavonoid, Luteolin, Negatively Affects Neuronal Differentiation.

Swaminathan Amrutha A Basu Moumita M Bekri Abdelhamid A Drapeau Pierre P Kundu Tapas K TK

Frontiers in molecular neuroscience 20190308

Luteolin, a polyphenolic plant flavonoid, has been attributed with numerous beneficial properties like anti-cancer, antioxidant, and anti-inflammatory action. Luteolin has been reported earlier to be neuroprotective in models of spinal cord injury and traumatic brain injury and also induces neurite outgrowth in PC12 cells. However, the effect of luteolin on early differentiation, which might be important for its beneficial effects, is unknown. In this report, we show that luteolin negatively aff ...[more]

PMID: 30906251

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Project description:Neuronal differentiation is exquisitely controlled both spatially and temporally during nervous system development. Defects in the spatiotemporal control of neurogenesis cause incorrect formation of neural networks and lead to neurological disorders such as epilepsy and autism. The mTOR kinase integrates signals from mitogens, nutrients and energy levels to regulate growth, autophagy and metabolism. We previously identified the insulin receptor (InR)/mTOR pathway as a critical regulator of the timing of neuronal differentiation in the Drosophila melanogaster eye. Subsequently, this pathway has been shown to play a conserved role in regulating neurogenesis in vertebrates. However, the factors that mediate the neurogenic role of this pathway are completely unknown. To identify downstream effectors of the InR/mTOR pathway we screened transcriptional targets of mTOR for neuronal differentiation phenotypes in photoreceptor neurons. We identified the conserved gene unkempt (unk), which encodes a zinc finger/RING domain containing protein, as a negative regulator of the timing of photoreceptor differentiation. Loss of unk phenocopies InR/mTOR pathway activation and unk acts downstream of this pathway to regulate neurogenesis. In contrast to InR/mTOR signalling, unk does not regulate growth. unk therefore uncouples the role of the InR/mTOR pathway in neurogenesis from its role in growth control. We also identified the gene headcase (hdc) as a second downstream regulator of the InR/mTOR pathway controlling the timing of neurogenesis. Unk forms a complex with Hdc, and Hdc expression is regulated by unk and InR/mTOR signalling. Co-overexpression of unk and hdc completely suppresses the precocious neuronal differentiation phenotype caused by loss of Tsc1. Thus, Unk and Hdc are the first neurogenic components of the InR/mTOR pathway to be identified. Finally, we show that Unkempt-like is expressed in the developing mouse retina and in neural stem/progenitor cells, suggesting that the role of Unk in neurogenesis may be conserved in mammals.

Project description:Mitochondrial membrane Protein Associated Neurodegeneration (MPAN) is a rare genetic disorder due to mutations in C19orf12 gene. In most cases, the disorder is transmitted as an autosomal recessive trait and the main clinical features are progressive spastic para/tetraparesis, dystonia, motor axonal neuropathy, parkinsonisms, psychiatric symptoms, and optic atrophy. Besides iron accumulation in the globus pallidus and substantia nigra, the neuropathology shows features also observed in Parkinson's Disease brains, such as α-synuclein-positive Lewy bodies and hyperphosphorylated tau. Mutations in the gene have been found in other neurodegenerative disorders, including PD, hereditary spastic paraplegia, pallido-pyramidal syndrome, and amyotrophic lateral sclerosis. The biological function of C19orf12 gene is poorly defined. In humans, it codes for two protein isoforms: the longer one is present in mitochondria, endoplasmic reticulum, and contact regions between mitochondria and ER. Mutations in the gene appear to be linked to defects in mitochondrial activity, lipid metabolism and autophagy/mitophagy. To increase the available tools for the investigation of MPAN pathogenesis, we generated a new animal model in zebrafish embryos. The zebrafish genome contains four co-orthologs of human C19orf12. One of them, located on chromosome 18, is expressed at higher levels at early stages of development. We downregulated its expression by microinjecting embryos with a specific ATG-blocking morpholino, and we analyzed embryonal development. Most embryos showed morphological defects such as unsettled brain morphology, with smaller head and eyes, reduced yolk extension, tilted and thinner tail. The severity of the defects progressively increased and all injected embryos died within 7 days post fertilization. Appropriate controls confirmed the specificity of the observed phenotype. Changes in the expression and distribution of neural markers documented a defective neuronal development, particularly evident in the eyes, the optic tectum, the midbrain-hindbrain boundary; Rohon Beard and dorsal root ganglia neurons were also affected. Phalloidin staining evidenced a significant perturbation of musculature formation that was associated with defective locomotor behavior. These data are consistent with the clinical features of MPAN and support the validity of the model to investigate the pathogenesis of the disease and evaluate molecules with potential therapeutic effect.

Dataset Information

The Dietary Flavonoid, Luteolin, Negatively Affects Neuronal Differentiation.

Publications

The Dietary Flavonoid, Luteolin, Negatively Affects Neuronal Differentiation.

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