Long Non-coding RNA Maternally Expressed 3 Increases the Expression of Neuron-Specific Genes by Targeting miR-128-3p in All-Trans Retinoic Acid-Induced Neurogenic Differentiation From Amniotic Epithelial Cells

Abstract

MicroRNA (miR)-128-3p is a brain-enriched miRNA that participates in the regulation of neural cell differentiation and the protection of neurons, but the mechanisms by which miR-128-3p regulates its target and downstream genes to influence cell fate from adult stem cells are poorly understood. In this study, we show down-regulation of miR-128-3p during all-trans retinoic acid (ATRA)-induced neurogenic differentiation from amniotic epithelial cells (AECs). We investigated miR-128-3p in both the Notch pathway and in the expression of neuron-specific genes predicted to be involved in miR-128-3p signaling to elucidate its role in the genetic regulation of downstream neurogenic differentiation. Our results demonstrate that miR-128-3p is a negative regulator for the transcription of the neuron-specific genes β III-tubulin, neuron-specific enolase (NSE), and polysialic acid-neural cell adhesion molecule (PSA-NCAM) via targeting Jagged 1 to inhibit activation of the Notch signaling pathway. We also used bioinformatics algorithms to screen for miR-128-3p interactions with long non-coding (lnc) RNA and circular RNA as competing endogenous RNAs to further elucidate underlying downregulated molecular mechanisms. The lncRNA maternally expressed 3 is up-regulated by the ATRA/cAMP/CREB pathway, and it, in turn, is directly down-regulated by miR-128-3p to increase the amount of neuron differentiation. Endogenous miRNAs are, therefore, involved in neurogenic differentiation from AECs and should be considered during the development of effective cell transplant therapies for the treatment of neurodegenerative disease.

LncRNA MALAT1 targeting miR‐124‐3p regulates DAPK1 expression contributes to cell apoptosis in Parkinson's Disease

“…However, the reports about lncRNAs in PD is relatively less. Accumulation research have indicated that lncRNAs serve as miRNAs “sponges” to influence gene expression base on the ceRNA regulation theory 18‐20 . lncRNA SNHG1 sponges miR‐15b‐5p triggers SIAH1 activation and further leads to α‐synuclein aggregation and neurotoxicity 21 .…”

“…Accumulation research have indicated that lncRNAs serve as miRNAs "sponges" to influence gene expression base on the ceRNA regulation theory. [18][19][20] lncRNA SNHG1 sponges miR-15b-5p triggers SIAH1 activation and further leads to α-synuclein aggregation and neurotoxicity. 21 Likewise, RAB3IP induces HOTAIR acts as a sponge of miR-126-5p aggravates the progression of PD.…”

The Emerging Roles of Long Non-Coding RNAs in Intellectual Disability and Related Neurodevelopmental Disorders

“…The lncRNA MEG3 is upregulated by the cAMP/response element-binding protein (CREB) pathway to increase the expression of neuron-specific genes and act as a ceRNA, influencing the expression of miR-128-3p [ 82 ].…”

Non-Coding RNAs in Retinoic Acid as Differentiation and Disease Drivers

“…Meg3 positively modulates neural markers, by acting as a sponge for miR-128, which in turn represses β-III tubulin, neuron-specific enolase (NSE) and polysialic acid neural cell adhesion molecule (PSA-NCAM) mRNA levels. The de-repression of these neuron-specific genes by Meg3 promotes and increases the number of neurons, suggesting a critical role for this lncRNA in neural differentiation and nervous system development [ 114 ]. Similar to Meg3 , Hotairm1 is upregulated by RA in a differentiation context, i.e., granulocytic differentiation.…”