miR-34b/c Regulates Wnt1 and Enhances Mesencephalic Dopaminergic Neuron Differentiation

Gregorio, Roberto De; Pulcrano, Salvatore; Sanctis, Claudia De; Volpicelli, Floriana; Guatteo, Ezia; Oerthel, Lars von; Latagliata, Emanuele Claudio; Esposito, Roberta; Piscitelli, Rosa Maria; Perrone-Capano, Carla; Costa, Valerio; Greco, Dario; Puglisi-Allegra, Stefano; Smidt, Marten P.; Porzio, Umberto di; Caiazzo, Massimiliano; Mercuri, Nicola Biagio; Li, Meng; Bellenchi, Gian Carlo

doi:10.1016/j.stemcr.2018.02.006

Cited by 45 publications

(63 citation statements)

References 53 publications

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“…MicroRNAs (miRNAs) are a class of evolutionary conserved small non-coding single-strand RNA molecules, 18–25 nucleotide long, able to bind to 3′ untranslated regions (3′ UTR) of target mRNAs and promote their degradation or suppress their translation into proteins. MiRNAs are expressed abundantly within the nervous system in a tissue-specific manner and are crucial players in several biological processes, including neurogenesis, neuronal maturation, synapse formation, axon guidance, neurite outgrowth and neuronal plasticity [ 51 , 52 , 53 ]. Accumulating data indicate that synthesis of BDNF may be affected by miRNAs, indeed, a regulatory negative feedback loop between BDNF and miRNAs exists.…”

Section: The Human Bdnf Gene: Transcripts and Variantsmentioning

confidence: 99%

Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer

Colucci-D’Amato

Speranza

Volpicelli

2020

IJMS

Self Cite

515

249

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Brain-derived neurotrophic factor (BDNF) is one of the most distributed and extensively studied neurotrophins in the mammalian brain. BDNF signals through the tropomycin receptor kinase B (TrkB) and the low affinity p75 neurotrophin receptor (p75NTR). BDNF plays an important role in proper growth, development, and plasticity of glutamatergic and GABAergic synapses and through modulation of neuronal differentiation, it influences serotonergic and dopaminergic neurotransmission. BDNF acts as paracrine and autocrine factor, on both pre-synaptic and post-synaptic target sites. It is crucial in the transformation of synaptic activity into long-term synaptic memories. BDNF is considered an instructive mediator of functional and structural plasticity in the central nervous system (CNS), influencing dendritic spines and, at least in the hippocampus, the adult neurogenesis. Changes in the rate of adult neurogenesis and in spine density can influence several forms of learning and memory and can contribute to depression-like behaviors. The possible roles of BDNF in neuronal plasticity highlighted in this review focus on the effect of antidepressant therapies on BDNF-mediated plasticity. Moreover, we will review data that illustrate the role of BDNF as a potent protective factor that is able to confer protection against neurodegeneration, in particular in Alzheimer’s disease. Finally, we will give evidence of how the involvement of BDNF in the pathogenesis of brain glioblastoma has emerged, thus opening new avenues for the treatment of this deadly cancer.

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Section: The Human Bdnf Gene: Transcripts and Variantsmentioning

confidence: 99%

Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer

Colucci-D’Amato

Speranza

Volpicelli

2020

IJMS

Self Cite

515

249

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“…The GFP-miR-218 construct was generated by cloning 400 bps encompassing the sequence for miR-218-1 into a Tet-O-FUW-Ires-GFP vector under the control of the tetracycline operator. Proper expression of mature miR-218 was tested by TaqMan (Thermo Fisher Scientific, Monza, Italy) assay as previously described [64]. Transfection was performed in combination with the rtTA transactivator supplied with doxycycline (2 mg/mL, Clontech, Mountain View, California, USA).…”

Section: Plasmidsmentioning

confidence: 99%

miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase

Rita

Maiorino

Bruqi

et al. 2020

IJMS

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The selective elimination of dysfunctional mitochondria through mitophagy is crucial for preserving mitochondrial quality and cellular homeostasis. The most described mitophagy pathway is regulated by a positive ubiquitylation feedback loop in which the PINK1 (PTEN induced kinase 1) kinase phosphorylates both ubiquitin and the E3 ubiquitin ligase PRKN (Parkin RBR E3 ubiquitin ligase), also known as PARKIN. This event recruits PRKN to the mitochondria, thus amplifying ubiquitylation signal. Here we report that miR-218 targets PRKN and negatively regulates PINK1/PRKN-mediated mitophagy. Overexpression of miR-218 reduces PRKN mRNA levels, thus also reducing protein content and deregulating the E3 ubiquitin ligase action. In fact, following miR-218 overexpression, mitochondria result less ubiquitylated and the autophagy machinery fails to proceed with correct mitochondrial clearance. Since mitophagy defects are associated with various human diseases, these results qualify miR-218 as a promising therapeutic target for human diseases.

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“…For instance, miR-34b/c is upregulated during DAergic differentiation and synergizes with ASC1 or Nurr1 transcription factors. 52 miR-133b is exclusively expressed in healthy midbrain DAergic neurons and regulates their maturation/function via negative feedback circuit that involves Pitx3. 53 The expression of miR-133b is lost in PD midbrain.…”

Section: Underlying Molecular Mechanismsmentioning

confidence: 99%

Complementation of dopaminergic signaling by Pitx3–GDNF synergy induces dopamine secretion by multipotent Ntera2 cells

Boroujeni

Aliaghaei

Maghsoudi

et al. 2019

J of Cellular Biochemistry

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Human teratocarcinoma cell line Ntera2 (NT2) expresses dopamine signals and has shown its safe profile for clinical applications. Attempts to restore complete dopaminergic (DAergic) phenotype enabling these cells to secrete dopamine have not been fully successful so far. We applied a blend of gene transfer techniques and a defined medium to convert NT2 cells to fully DAergic. The cells were primarily engineered to overexpress the Pitx3 gene product and then cultured in a growth medium supplemented with knockout serum and retinoic acid to form embroid bodies (EBs). Trypsinization of EB colonies produced single cells ready for differentiation. Neuronal/DAergic induction was promoted by applying conditioned medium taken from engineered human astrocytomas over‐secreting glial cell‐derived neurotrophic factor (GDNF). Immunocytochemistry, reverse‐transcription and real‐time polymerase chain reaction analyses confirmed significantly induced expression of molecules involved in dopamine signaling and metabolism including tyrosine hydroxylase, Nurr1, dopamine transporter, and aromatic acid decarboxylase. High‐performance liquid chromatography analysis indicated release of dopamine only from a class of fully differentiated cells expressing Pitx3 and exposed to GDNF. In addition, Pitx3 and GDNF additively promoted in vitro neuroprotection against Parkinsonian toxin. One month after transplantation to the striatum of 6‐OHDA‐leasioned rats, differentiated NT2 cells survived and induced significant increase in striatal volume. Besides, cell implantation improved motor coordination in Parkinson's disease (PD) rat models. Our findings highlight the importance of Pitx3–GDNF interplay in dopamine signaling and indicate that our strategy might be useful for the restoration of DAergic fate of NT2 cells to make them clinically applicable toward cell replacement therapy of PD.

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miR-34b/c Regulates Wnt1 and Enhances Mesencephalic Dopaminergic Neuron Differentiation

Cited by 45 publications

References 53 publications

Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer

Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer

miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase

Complementation of dopaminergic signaling by Pitx3–GDNF synergy induces dopamine secretion by multipotent Ntera2 cells

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