Neuroimmunology Unit, INSpe, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Cell Death Dis. 2012 Aug 2;3(8):e360. doi: 10.1038/cddis.2012.98.
The precise mechanisms by which microRNAs (miRNAs) contribute to the dynamic regulation of gene expression during the forebrain development are still partly elusive. Here we show that the depletion of miRNAs in the cerebral cortex and hippocampus, via genetic inactivation of Dicer after the onset of forebrain neurogenesis, profoundly impairs the morphological and proliferative characteristics of neural stem and progenitor cells. The cytoarchitecture and self-renewal potential of radial glial (RG) cells located within the cerebral cortex and the hippocampus were profoundly altered, thus causing a significant derangement of both the post natal dorsal sub-ventricular zone and the dentate gyrus. This effect was attributed to the High-temperature requirement A serine peptidase 1 (HtrA1) gene product whose overexpression in the developing forebrain recapitulated some of the aspects of the Dicer(-/-) phenotype. MiR-30e and miR-181d were identified as posttranscriptional negative regulators of HtrA1 by binding to its 3' untranslated region. In vivo overexpression of miR-30e and miR-181d in Dicer(-/-) forebrain rescued RG proliferation defects.
miRNAs 在大脑皮质和海马体中的缺失通过神经发生后 Dicer 的基因失活，极大地损害了神经干细胞和祖细胞的形态和增殖特征。位于大脑皮质和海马体中的放射状胶质 (RG) 细胞的细胞结构和自我更新潜能发生了深刻变化，从而导致出生后背侧脑室下区和齿状回的明显紊乱。这种影响归因于高温需求 A 丝氨酸肽酶 1 (HtrA1) 基因产物，其在发育中的前脑中的过表达再现了 Dicer(-/-) 表型的某些方面。miR-30e 和 miR-181d 通过与其 3'非翻译区结合成为 HtrA1 的转录后负调控因子。在 Dicer(-/-) 前脑中的 miR-30e 和 miR-181d 的体内过表达挽救了 RG 增殖缺陷。
