Abstract
During cortical development, neuronal migration is one of the most important steps for normal cortical formation and function, and defects in this process cause many brain diseases. However, the molecular mechanisms underlying this process remain largely unknown. In this study, we found that miR-129-5p and miR-129-3p were expressed in both neural progenitor cells and cortical neurons in the developing murine cortex. Moreover, abnormal miR-129 expression could block radial migration of both the deeper layer and upper layer neurons, and impair the multipolar to bipolar transition. However, antagomir-mediated inhibition resulted in overmigration of neurons. In addition, we showed that Fragile X Mental Retardation gene 1 (Fmr1), which is mutated in the autism spectrum disorder fragile X syndrome, is an important regulatory target for miR-129-5p. Furthermore, Fmr1 loss-of-function and gain-of-function experiments showed opposite effects on miR-129 regulation of neuronal migration, and restoring Fmr1 expression could counteract the deleterious effect of miR-129 on neuronal migration. Taken together, our results suggest that miR-129-5p could modulate the expression of fragile X mental retardation 1 protein (FMRP) to ensure normal neuron positioning in the developing cerebral cortex.
Highlights
The mammalian neocortex is highly organised into a sixlayered structure and involved in a variety of higher cognitive, sensory, emotional, and motor functions
We have found that both miR-129-5p and miR-129-3p are expressed in neural progenitor cells (NPCs) and cortical neurons during cortical neurogenesis
We performed in situ hybridization (ISH) experiments with miRNA probes modified by locked nucleic acid (LNA)[43] complementary to the mature miRNA to ascertain their expression patterns in the developing neocortex at E14.5 and E16.5
Summary
The mammalian neocortex is highly organised into a sixlayered structure and involved in a variety of higher cognitive, sensory, emotional, and motor functions. Radial glial cells (RGCs) in MicroRNAs (miRNAs) are endogenous ~22 nucleotide noncoding RNAs that can bind to the 3′ untranslated region (3′UTR) of target mRNAs and mediate their degradation or translation inhibition[18]. Official journal of the Cell Death Differentiation Association. Many miRNAs have been shown to be involved in regulating neuronal stem cell proliferation and differentiation[19,20,21,22,23,24,25], whether miRNAs are involved in neuronal migration remains unknown. MiR379-410 cluster miRNAs were reported to regulate neuronal migration by fine-tuning N-cadherin[27]. MiR-22 and miR-124 promoted radial migration by targeting CoREST28. MiR-128 was shown to regulate neuronal migration by binding to the 3′UTR of Phf[629]
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