Long non-coding RNAs in corticogenesis: deciphering the non-coding code of the brain

Abstract

Evidence on the role of long non-coding (lnc) RNAs has been accumulating over decades, but it has been only recently that advances in sequencing technologies have allowed the field to fully appreciate their abundance and diversity. Despite this, only a handful of lncRNAs have been phenotypically or mechanistically studied. Moreover, novel lncRNAs and new classes of RNAs are being discovered at growing pace, suggesting that this class of molecules may have functions as diverse as protein-coding genes. Interestingly, the brain is the organ where lncRNAs have the most peculiar features including the highest number of lncRNAs that are expressed, proportion of tissue-specific lncRNAs and highest signals of evolutionary conservation. In this work, we critically review the current knowledge about the steps that have led to the identification of the non-coding transcriptome including the general features of lncRNAs in different contexts in terms of both their genomic organisation, evolutionary origin, patterns of expression, and function in the developing and adult mammalian brain.

Keywords: brain development; long non‐coding RNAs; neural stem cells.

Figure 1. Possible genomic arrangements of lncRNAs with respect to their neighbouring genes

Diagrams displaying different arrangements of coding (black) and neighbouring lncRNA (green) genes. Similar arrangements can be found for coding–coding and non‐coding–non‐coding gene pairs. Arrows indicate direction of transcription.

Figure 2. LncRNAs regulate different stages of neurogenesis and gliogenesis

Diagram summarising the lineage of neural stem cells during mammalian corticogenesis (top) and roles of lncRNAs studied thus far (middle). (Top) Arrows indicate proliferative (circle) or differentiative (line) divisions with the main cellular processes being indicated underneath each cell type. (Middle) Phenotypic outputs of manipulated lncRNAs through gain or loss of function (GOF or LOF, respectively) are indicated as an increase (upward arrow) or decrease (downward arrow) of the corresponding cellular process. White box (bottom) summarises lncRNAs regulating alternative cell fates.

Figure 3. LncRNAs regulate transcriptional and posttranscriptional factors involved in neurogenesis

Representation of molecular mechanisms underlying the function of lncRNAs involved in corticogenesis. Examples include regulation of transcription factors (A–G), regulation of morphogens (H), chromatin remodelling (D, I) and splicing (I, J). In each case, coding (black) and non‐coding (green) genes (thick arrows), transcripts (lines) or proteins (coloured circles) are indicated including their known or suggested interactions (arrows indicate activation/induction; blocked lines indicate repression; dashed lines indicate unknown mechanism). TF: other transcription factors (I: adapted from Lin et al, 2014).