Department of Cell and Developmental Biology, Weill Medical College, Cornell University, New York, New York, United States of America.
PLoS One. 2011;6(10):e26000. doi: 10.1371/journal.pone.0026000. Epub 2011 Oct 4.
The adult hippocampus consists of the dentate gyrus (DG) and the CA1, CA2 and CA3 regions and is essential for learning and memory functions. During embryonic development, hippocampal neurons are derived from hippocampal neuroepithelial cells and dentate granular progenitors. The molecular mechanisms that control hippocampal progenitor proliferation and differentiation are not well understood. Here we show that noncoding microRNAs (miRNAs) are essential for early hippocampal development in mice. Conditionally ablating the RNAase III enzyme Dicer at different embryonic time points utilizing three Cre mouse lines causes abnormal hippocampal morphology and affects the number of hippocampal progenitors due to altered proliferation and increased apoptosis. Lack of miRNAs at earlier stages causes early differentiation of hippocampal neurons, in particular in the CA1 and DG regions. Lack of miRNAs at a later stage specifically affects neuronal production in the CA3 region. Our results reveal a timing requirement of miRNAs for the formation of specific hippocampal regions, with the CA1 and DG developmentally hindered by an early loss of miRNAs and the CA3 region to a late loss of miRNAs. Collectively, our studies indicate the importance of the Dicer-mediated miRNA pathway in hippocampal development and functions.
成年海马体由齿状回（DG）和 CA1、CA2 和 CA3 区域组成，对学习和记忆功能至关重要。在胚胎发育过程中，海马神经元来源于海马神经上皮细胞和齿状颗粒祖细胞。控制海马祖细胞增殖和分化的分子机制尚不清楚。在这里，我们表明非编码 microRNAs（miRNAs）对于小鼠早期海马体发育至关重要。利用三种 Cre 小鼠系在不同的胚胎时间点条件性地敲除 RNAase III 酶 Dicer 会导致海马体形态异常，并由于增殖改变和凋亡增加而影响海马祖细胞的数量。miRNAs 在早期阶段的缺乏会导致海马神经元的早期分化，特别是在 CA1 和 DG 区域。miRNAs 在后期的缺乏会特异性地影响 CA3 区域的神经元产生。我们的结果揭示了 miRNAs 对于特定海马区域形成的时间要求，CA1 和 DG 区域由于早期缺乏 miRNAs 而发育受阻，而 CA3 区域由于晚期缺乏 miRNAs 而受到影响。总的来说，我们的研究表明 Dicer 介导的 miRNA 途径在海马体发育和功能中的重要性。
