Abstract
The porcine brain closely resembles the human brain in aspects such as development and morphology. Temporal miRNA profiling in the developing embryonic porcine cortex revealed a distinct set of miRNAs, including miR-34c and miR-204, which exhibited a highly specific expression profile across the time of cortical folding. These miRNAs were found to target Doublecortin (DCX), known to be involved in neuron migration during cortical folding of gyrencephalic brains. In vivo modulation of miRNA expression in mouse embryos confirmed that miR-34c and miR-204 can control neuronal migration and cortical morphogenesis, presumably by posttranscriptional regulation of DCX.
Highlights
Over the course of evolution, the mammalian brain has grown, both in volume and surface
Among the top 5 most significantly affected genes, DCX is of particular interest since it has been implicated in migration of cortical neurons, and is a prime target for miRNA-mediated control in respect to cortical morphogenesis
Further support for a conserved functional relationships between DCX and miR-204/34c as well as LIS1 and miR-15a comes from the observation that the respective miRNAs can regulate luciferase expression under control of human derived DCX and LIS1 3′UTRs
Summary
Over the course of evolution, the mammalian brain has grown, both in volume and surface. A high level of asymmetrical cell division of radial glial cells occurs, resulting in both new radial glial cells and more differentiated daughter cells, including neurons (Sun and Hevner, 2014) Following this step, proper lamination is primarily ensured by regulated migration of neurons and intermediate progenitors, toward the pial surface of the cortex, closest to the skull. Knockdown of DCX in utero inhibits migration of cortical neurons (Kriegstein and Noctor, 2004) Based on these lissencephaly disease models a picture emerges supporting cytoskeleton arrangement and neuronal migration as essential components of normal brain development in gyrencephalic species. MiR-128 was shown to affect migration by regulating PHF6 (Franzoni et al, 2015) These miRNAs are not sharply regulated at the time of cortical folding, suggesting that, functionally important, they are not key regulators of the process. Combined with our discovery that these two miRNAs show extreme expression differences across cortical folding in the pig, suggests that they are instrumental in establishing the correct cortical morphogenesis in gyrencephalic animals
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