Abstract
MicroRNAs (miRNAs), one of the major small non-coding RNA classes, have been proposed as regulatory molecules in neurodevelopment and stress response. Although alterations in miRNAs profiles have been implicated in several psychiatric and neurodevelopmental disorders, the contribution of individual miRNAs in brain development and function is still unknown. Recent studies have identified miR-19 as a key regulator of brain trajectories, since it drives the differentiation of neural stem cells into mature neurons. However, no findings are available on how vulnerability factors for these disorders, such as early life stress (ELS), can modulate the expression of miR-19 and its target genes. To reach our aim, we investigated miR-19 modulation in human hippocampal progenitor stem cells (HPCs) treated with cortisol during 3 days of proliferation and harvested immediately after the end of the treatment or after 20 days of differentiation into mature neurons. We also analyzed the long-term expression changes of miR-19 and of its validated target genes, involved in neurodevelopment and inflammation, in the hippocampus of adult rats exposed or not to prenatal stress (PNS). Interestingly, we observed a significant downregulation of miR-19 levels both in proliferating (FC = −1.59, p-value = 0.022 for miR-19a; FC = −1.79, p-value = 0.016 for miR-19b) as well as differentiated HPCs (FC = −1.28, p-value = 0.065 for miR-19a; FC = −1.75, p-value = 0.047 for miR-19b) treated with cortisol. Similarly, we found a long-term decrease of miR-19 levels in the hippocampus of adult PNS rats (FC = −1.35, p-value = 0.025 for miR-19a; FC = −1.43, p-value = 0.032 for miR-19b). Among all the validated target genes, we observed a significant increase of NRCAM (FC = 1.20, p-value = 0.027), IL4R (FC = 1.26, p-value = 0.046), and RAPGEF2 (FC = 1.23, p-value = 0.020).We suggest that ELS can cause a long-term downregulation of miR-19 levels, which may be responsible of alterations in neurodevelopmental pathways and in immune/inflammatory processes, leading to an enhanced risk for mental disorders later in life. Intervention strategies targeting miR-19 may prevent alterations in these pathways, reducing the ELS-related effects.
Highlights
MicroRNAs represent one of the major small noncoding RNA classes that have been proposed as regulatory molecules in several biological processes, including neurodevelopment and stress response [1,2,3,4]
With the aim to investigate the effects of early life stress (ELS) on the modulation of miR-19a and miR-19b, we used our well-established in vitro model of stress represented by the HPC0A07/03C cells that we treated with the stress hormone cortisol 100 mM [20, 40, 45]
We observed that an exposure to ELS produces a short and long-term effect on miR-19 modulation, which in turn may affect normal trajectories of brain development and neuronal networks formation, increasing the vulnerability to develop psychiatric disorders later in life
Summary
MicroRNAs (miRNAs) represent one of the major small noncoding RNA classes that have been proposed as regulatory molecules in several biological processes, including neurodevelopment and stress response [1,2,3,4]. They are critical regulators of gene expression and exert their activity through the modulation of target mRNA stability or translation efficiency. The miRNA binding, primarily to the 3′UTR of mRNAs, leads to mRNA destabilization or translational repression, resulting in reduced protein levels of the miRNA-target genes [5]. The potential role of epigenetic deregulation in the pathogenesis of psychiatric disorders is a major focus of the current research [15, 16], the contribution of individual miRNAs in brain development and function and, in the pathophysiology of psychiatric illnesses is still largely unknown
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