Emerging Roles of miRNAs in Brain Development and Perinatal Brain Injury

Abstract

In human beings the immature brain is highly plastic and depending on the stage of gestation is particularly vulnerable to a range of insults that if sufficiently severe, can result in long-term motor, cognitive and behavioral impairment. With improved neonatal care, the incidence of major motor deficits such as cerebral palsy has declined with prematurity. Unfortunately, however, milder forms of injury characterized by diffuse non-cystic white matter lesions within the periventricular region and surrounding white matter, involving loss of oligodendrocyte progenitors and subsequent axonal hypomyelination as the brain matures have not. Existing therapeutic options for treatment of preterm infants have proved inadequate, partly owing to an incomplete understanding of underlying post-injury cellular and molecular changes that lead to poor neurodevelopmental outcomes. This has reinforced the need to improve our understanding of brain plasticity, explore novel solutions for the development of protective strategies, and identify biomarkers. Compelling evidence exists supporting the involvement of microRNAs (miRNAs), a class of small non-coding RNAs, as important post-transcriptional regulators of gene expression with functions including cell fate specification and plasticity of synaptic connections. Importantly, miRNAs are differentially expressed following brain injury, and can be packaged within exosomes/extracellular vesicles, which play a pivotal role in assuring their intercellular communication and passage across the blood–brain barrier. Indeed, an increasing number of investigations have examined the roles of specific miRNAs following injury and regeneration and it is apparent that this field of research could potentially identify protective therapeutic strategies to ameliorate perinatal brain injury. In this review, we discuss the most recent findings of some important miRNAs in relation to the development of the brain, their dysregulation, functions and regulatory roles following brain injury, and discuss how these can be targeted either as biomarkers of injury or neuroprotective agents.

Neuroprotective effects of human amniotic fluid stem cells-derived secretome in an ischemia/reperfusion model

“…CoREST/REST complex, 101 and miR-27a is involved in controlling neuroinflammation. 99 Also, among the other miRNA identified, miR-29a was already described to protect against cell damage after ischemia-like stress and astrocyte ischemic injury 102,103 ; miR-31-5p, also identified in our exosomal component, is known to reduce the inflammatory response and oxidative stress-induced neuronal damage 104 and, further, shows pro-angiogenic activity. 105 On the other hand, regarding other miRNAs here identified, such as miR-221-3p, miR-222-3p, miR-24-3p, and miR-28-5p, limited or conflicting data about their function and implication in neuronal processes have been reported.…”

The microRNA-17 ~ 92 Family as a Key Regulator of Neurogenesis and Potential Regenerative Therapeutics of Neurological Disorders

“…After being expressed, miRNAs predominantly serve as a post-transcriptional silencer via either inducing the degradation of certain transcripts or interfering with translation process by binding to the 3' untranslated region (UTR) of transcripts [10]. miRNAs have emerged as a crucial regulator in both development and adult neurogenesis [7,[11][12][13][14]. The cortex-specific knockout (KO) of Dicer, a key enzyme for miRNA biogenesis, significantly reduces the cellular complexity during cerebral cortex development [15].…”

Verbal memory dysfunction is associated with alterations in brain transcriptome in dominant temporal lobe epilepsy

“…miRNAs represent a class of small noncoding RNAs that regulate gene expression posttranscriptionally by destabilizing, degrading, or silencing mRNAs. miRNAs have been shown to play a pivotal role in nervous system development, 45 synaptic plasticity, 18 and learning and memory, 18,19,46 as well as in the etiology of neurological disorders like Alzheimer disease and Parkinson disease. 19 Our findings suggest that miRNAs are upstream regulators of many of the observed DETs between brains from patients with and without memory impairment.…”