Abstract
MicroRNAs (miRNAs) are implicated in the epigenetic regulation of several brain developmental processes, such as neurogenesis, neuronal differentiation, neurite outgrowth, and synaptic plasticity. The main aim of this study was to evaluate whether miRNA expression profiling could be a useful approach to detect in vitro developmental neurotoxicity. For this purpose, we assessed the changes in miRNA expression caused by methyl mercury chloride (MeHgCl), a well-known developmental neurotoxicant, comparing carcinoma pluripotent stem cells (NT-2) with human embryonic stem cells (H9), both analyzed during the early stage of neural progenitor commitment into neuronal lineage. The data indicate the activation of two distinct miRNA signatures, one activated upon neuronal differentiation and another upon MeHgCl-induced toxicity. Particularly, exposure to MeHgCl elicited, in both neural models, the down-regulation of the same six out of the ten most up-regulated neuronal pathways, as shown by the up-regulation of the corresponding miRNAs and further assessment of gene ontology (GO) term and pathway enrichment analysis. Importantly, some of these common miRNA-targeted pathways defined in both cell lines are known to play a role in critical developmental processes, specific for neuronal differentiation, such as axon guidance and neurotrophin-regulated signaling. The obtained results indicate that miRNAs expression profiling could be a promising tool to assess developmental neurotoxicity pathway perturbation, contributing towards improved predictive human toxicity testing.
Highlights
Neuronal gene expression is tightly regulated during development of central nervous system (CNS).the process of neurogenesis requires the coordinated up regulation of neuronal genes and down-regulation of non-neuronal genes to ensure the proper timing of differentiation and correct number of neurons
To identify the possible developmental neurotoxicity testing (DNT) biomarkers among deregulated miRNAs, we have firstly studied the changes in miRNA expression during the process of neuronal differentiation in the neuronal cultures derived from H9 or NT-2 cell lines and compared the miRNA expression profiles in the same cell lines observed after exposure to a non-cytotoxic concentration of methyl mercury chloride (MeHgCl)
Six out of the ten most significant pathways involved in the response to MeHgCl treatment are shared between the two test systems. Some of these common miRNA-targeted pathways could play a role in critical developmental processes, specific for neuronal differentiation, such as axonal guidance or neurotrophin-related signaling pathways. These results suggest that similar pathways are affected by MeHgCl exposure in both neural cultures derived from NT-2 or H9 (Table 3) and, most importantly, these pathways are linked to neuronal cell function regulations
Summary
Neuronal gene expression is tightly regulated during development of central nervous system (CNS).the process of neurogenesis requires the coordinated up regulation of neuronal genes and down-regulation of non-neuronal genes to ensure the proper timing of differentiation and correct number of neurons. Neuronal gene expression is tightly regulated during development of central nervous system (CNS). A great deal of evidence showed that gene expression regulation includes, transcription factors, and small regulatory RNAs, such as microRNAs (miRNAs), which play an important role in the establishment and maintenance of cell identity, neuronal and glial differentiation, axonal path-finding, neuronal patterning, and plasticity [1,2,3]. MiRNAs introduce an additional layer of post-transcriptional regulatory control of gene expression since each miRNA can target up to a few hundred target genes, resulting in the regulation of as much as one third of the protein expression in animals [4]. The role of miRNAs in brain development has been studied by analyzing the effects of the genomic.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
