Tuncdemir Sebnem N, Fishell Gord, Batista-Brito Renata
NYU Neuroscience Institute and the Department of Neuroscience and Physiology, Smilow Research Center, New York University School of Medicine, New York, NY 10016, USA.
NYU Neuroscience Institute and the Department of Neuroscience and Physiology, Smilow Research Center, New York University School of Medicine, New York, NY 10016, USA Current Address: Department of Neurobiology, Yale University, PO Box 208001, New Haven, CT 06520-8001, USA.
Cereb Cortex. 2015 Jul;25(7):1842-57. doi: 10.1093/cercor/bht426. Epub 2014 Jan 22.
Complex and precisely orchestrated genetic programs contribute to the generation, migration, and maturation of cortical GABAergic interneurons (cIN). Yet, little is known about the signals that mediate the rapid alterations in gene expression that are required for cINs to transit through a series of developmental steps leading to their mature properties in the cortex. Here, we investigated the function of post-transcriptional regulation of gene expression by microRNAs on the development of cIN precursors. We find that conditional removal of the RNAseIII enzyme Dicer reduces the number of cINs in the adult mouse. Dicer is further necessary for the morphological and molecular maturation of cINs. Loss of mature miRNAs affects cINs development by impairing migration and differentiation of this cell type, while leaving proliferation of progenitors unperturbed. These developmental defects closely matched the abnormal expression of molecules involved in apoptosis and neuronal specification. In addition, we identified several miRNAs that are selectively upregulated in the postmitotic cINs, consistent with a role of miRNAs in the post-transcriptional control of the differentiation and apoptotic programs essential for cIN maturation. Thus, our results indicate that cIN progenitors require Dicer-dependent mechanisms to fine-tune the migration and maturation of cINs.
复杂且精确编排的基因程序有助于皮质γ-氨基丁酸能中间神经元（cIN）的产生、迁移和成熟。然而，对于介导cIN在皮质中经历一系列发育步骤以获得其成熟特性所需的基因表达快速变化的信号，我们却知之甚少。在此，我们研究了微小RNA对基因表达的转录后调控在cIN前体发育中的作用。我们发现，条件性去除核糖核酸酶III（RNAseIII）酶Dicer会减少成年小鼠中cIN的数量。Dicer对于cIN的形态和分子成熟也是必需的。成熟微小RNA的缺失通过损害这种细胞类型的迁移和分化来影响cIN的发育，而祖细胞的增殖则不受影响。这些发育缺陷与参与细胞凋亡和神经元特化的分子的异常表达密切匹配。此外，我们鉴定出了几种在有丝分裂后cIN中选择性上调的微小RNA，这与微小RNA在转录后控制cIN成熟所必需的分化和凋亡程序中的作用一致。因此，我们的结果表明，cIN祖细胞需要依赖Dicer的机制来微调cIN的迁移和成熟。
