A Primate lncRNA Mediates Notch Signaling during Neuronal Development by Sequestering miRNA

Highlights

  • Identification of LncND with a Catarrhine insertion of 16 MREs for miR-143-3p
  • LncND regulates expression of Notch genes by sequestering miR-143-3p
  • High expression of LncND in radial glia cells in human VZ and OSVZ
  • LncND appears to be involved in the expansion of radial glia cells in primates

Long non-coding RNAs (lncRNAs) are a diverse and poorly conserved category of transcripts that have expanded greatly in primates, particularly in the brain. Researchers at UC Santa Barbara identified an lncRNA, which has acquired 16 microRNA response elements for miR-143-3p in the Catarrhini branch of primates. This lncRNA, termed LncND (neurodevelopment), is expressed in neural progenitor cells and then declines in neurons. Binding and release of miR-143-3p by LncND control the expression of Notch receptors. LncND expression is enriched in radial glia cells (RGCs) in the ventricular and subventricular zones of developing human brain. Downregulation in neuroblastoma cells reduced cell proliferation and induced neuronal differentiation, an effect phenocopied by miR-143-3p overexpression. Gain of function of LncND in developing mouse cortex led to an expansion of PAX6+ RGCs. These findings support a role for LncND in miRNA-mediated regulation of Notch signaling within the neural progenitor pool in primates that may have contributed to the expansion of cerebral cortex.

Identification, Characterization, and Conservation of LncND Transcript

lncRNA

(A) Computational prediction (using TargetScan) of all the MREs of brain-expressed miRNAs on all the brain-expressed human lncRNAs (from Human Body Map lincRNAs). The graph represents the total lncRNAs having MREs ranging from 1 to 12.

(B) Diagrammatic representation of LncND transcript of 2,710 bp length as annotated on UCSC genome browser showing the MREs located in the 5′ end. Region between 1 and 1,971 bp of LncND transcript is zoomed-in to show the MREs for miR-143-3p, miR-4330, miR-1912, and miR-4286.

(C) ISH using probes specific for either sense (left) or antisense (right) strand. Brown dots represent the positive signal for LncND and blue staining shows the hematoxylin nuclear stain. Black and red arrows represent the cytoplasmic and nuclear expression of LncND, respectively. The experiment was repeated twice with the same outcome in neural progenitor cells (top) and SHSY5Y cells (bottom). Scale bar, 50 μm.

(D) Multiz Alignment showing the conservation of LncND across some representative species. Red bar represents the 5′ end of human LncND enriched in MREs for several miRNAs.

(E) Phylogenetic relationship of LncND among primates. Branch lengths are based on an approximation of the standard likelihood ratio test representing the number of substitutions per site calculated by PhyML. Numbers represented in red are branch support values. The tree was created using phylogeny.fr platform. The numbers of MREs for miR-143-3p are shown in green in parentheses.

Rani N, Nowakowski TJ, Zhou H, Godshalk SE, Lisi V, Kriegstein AR, Kosik KS. (2016) A Primate lncRNA Mediates Notch Signaling during Neuronal Development by Sequestering miRNA. Neuron [Epub ahead of print]. [abstract]

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