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The role of long noncoding RNAs in neurogenesis

  • Author(s): Ramos, Alexander Daniel
  • Advisor(s): Lim, Daniel A
  • et al.
Abstract

Long noncoding RNAs (lncRNAs) have been described in cell lines and various whole tissues, but lncRNA analysis of development in vivo is limited. Here, we comprehensively analyze lncRNA expression of the adult mouse subventricular zone neural stem cell lineage. We utilize complementary genome-wide techniques including RNA-seq, RNA CaptureSeq, and ChIP-seq to associate specific lncRNAs with neural cell types, developmental processes, and human disease states. By integrating data from chromatin state maps, custom microarrays, and FACS purification of the subventricular zone lineage, we stringently identify lncRNAs with potential roles in adult neurogenesis. shRNA-mediated knockdown of two such lncRNAs, Six3os and Dlx1as, indicate roles for lncRNAs in the glial-neuronal lineage specification of multipotent adult stem cells. Using our lncRNA pipeline, we identify Pinky (Pnky) as a long non-coding RNA (lncRNA) that regulates the transition between NSCs and neurogenic progenitors. Pnky is expressed in NSC populations and becomes downregulated during neurogenesis. shRNA-mediated knockdown of Pnky expands the pool of neurogenic progenitors, increasing neurogenesis. Pinky is conserved and expressed in NSCs of the developing mouse and human cortex. In embryonic mouse brain, Pnky knockdown accelerates neurogenesis and depletes this embryonic NSC population. Pnky physically interacts with PTBP1, a regulator of mRNA splicing, and Pnky depletion leads to the differential splicing of PTBP1 targets. These data thus identify Pinky as a conserved lncRNA that regulates a critical stage of neurogenesis from NSCs in the adult and embryonic brain. Taken together, our data forms the foundation of a resource for the study of lncRNAs in development and disease. In depth study of the novel lncRNA Pnky highlights the utility of this resource for the identification of lncRNAs that play key roles in neural lineage progression.

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