Abstract
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.
Highlights
The hippocampus is a well studied brain structure due to its ability to process learning and memory functions
MiRNA biogenesis was blocked in the developing hippocampus at different embryonic time points
We have found that early miRNA function is required for proper hippocampal morphogenesis, and that it is essential for continuous expansion of hippocampal neuroepithelial and dentate granular progenitors
Summary
The hippocampus is a well studied brain structure due to its ability to process learning and memory functions. Wnt3a is expressed in the cortical hem and its downstream gene Lef is expressed in the hippocampus. Previous studies have shown that Wnt3a and Lef mutant mice display severe hippocampal defects [12,13]. Transcription factors, such as Emx, expressed in hippocampal neuroepithelial cells; and Lhx, expressed in the cortical hem, are important for morphogenesis of the developing hippocampus [14,15,16]. The molecular mechanisms that control precise and dynamic expression of the molecules essential for hippocampal development remain unclear
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