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Abstract
MiR-451a is best known for its role in erythropoiesis and for its tumour suppressor features. Here we show a role for miR-451a in neuronal differentiation through analysis of endogenous and ectopically expressed or silenced miR-451a in Ntera2/D1 cells during neuronal differentiation. Furthermore, we compared neuronal differentiation in the dentate gyrus of hippocampus of miR-451a-/- and wild type mice. MiR-451a overexpression in lentiviral transduced Ntera2/D1 cells was associated with a significant shifting of mRNA expression of the developmental markers Nestin, βIII Tubulin, NF200, DCX and MAP2 to earlier developmental time points, compared to control vector transduced cells. In line with this, accelerated neuronal network formation in AB.G.miR-451a transduced cells, as well as an increase in neurite outgrowth both in number and length was observed. MiR-451a targets genes MIF, AKT1, CAB39, YWHAZ, RAB14, TSC1, OSR1, POU3F2, TNS4, PSMB8, CXCL16, CDKN2D and IL6R were, moreover, either constantly downregulated or exhibited shifted expression profiles in AB.G.miR-451a transduced cells. Lentiviral knockdown of endogenous miR-451a expression in Ntera2/D1 cells resulted in decelerated differentiation. Endogenous miR-451a expression was upregulated during development in the hippocampus of wildtype mice. In situ hybridization revealed intensively stained single cells in the subgranular zone and the hilus of the dentate gyrus of wild type mice, while genetic ablation of miR-451a was observed to promote an imbalance between proliferation and neuronal differentiation in neurogenic brain regions, suggested by Ki67 and DCX staining. Taken together, these results provide strong support for a role of miR-451a in neuronal maturation processes in vitro and in vivo.
Highlights
MiR-451a is a distinct dicer-independent miRNA that has been extensively studied in brain malignancies such as glioblastoma multiforme
Application of microparticles isolated from the cerebrospinal fluid (CSF) of traumatic brain injury (TBI) patients to Ntera2/D1 (NT2) cell cultures, led to a downregulation of CD133 and FGFR1 mRNA expression, which could be blocked by miR-451a antisense oligonucleotides, indicating miR-451a to be the main effector [5]
CD133 and FGFR1 have both been associated with cell proliferation [7–9] and miR-451a-mediated down-regulation of them in Ntera2/D1 (NT2), a cell line that differentiates along the neuroectodermal lineages after exposure to retinoic acid (RA) [10], might indicate a role of miR-451a in the onset of early differentiation of this neurogenic cell line
Summary
MiR-451a is a distinct dicer-independent miRNA that has been extensively studied in brain malignancies such as glioblastoma multiforme. A regulatory role of miR-451a in brain has been suggested by our own previous studies showing that microparticles derived from cerebrospinal fluid (CSF) of patients during the acute stages of traumatic brain injury (TBI) are enriched in miR-451a [5]. These observations are consistent with a study showing rapid down-regulation of miR-451a in a rat model of traumatic brain injury [6], which could potentially be evoked by the release of miR451a enriched microparticles into the cerebrospinal fluid [5]. Application of microparticles isolated from the CSF of TBI patients to Ntera2/D1 (NT2) cell cultures, led to a downregulation of CD133 and FGFR1 mRNA expression, which could be blocked by miR-451a antisense oligonucleotides, indicating miR-451a to be the main effector [5]. CD133 and FGFR1 have both been associated with cell proliferation [7–9] and miR-451a-mediated down-regulation of them in Ntera2/D1 (NT2), a cell line that differentiates along the neuroectodermal lineages after exposure to retinoic acid (RA) [10], might indicate a role of miR-451a in the onset of early differentiation of this neurogenic cell line
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