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Long Non-Coding RNA Lacuna Regulates Neuronal Differentiation of Neural Stem Cells During Brain Development.

ABSTRACT: Although long non-coding RNAs (lncRNAs) is one of the most abundant classes of RNAs encoded within the mammalian genome and are highly expressed in the adult brain, they remain poorly characterized and their roles in the brain development are not well understood. Here we identify the lncRNA Lacuna (also catalogued as NONMMUT071331.2 in NONCODE database) as a negative regulator of neuronal differentiation in the neural stem/progenitor cells (NSCs) during mouse brain development. In particular, we show that Lacuna is transcribed from a genomic locus near to the Tbr2/Eomes gene, a key player in the transition of intermediate progenitor cells towards the induction of neuronal differentiation. Lacuna RNA expression peaks at the developmental time window between E14.5 and E16.5, consistent with a role in neural differentiation. Overexpression experiments in ex vivo cultured NSCs from murine cortex suggest that Lacuna is sufficient to inhibit neuronal differentiation, induce the number of Nestin+ and Olig2+ cells, without affecting proliferation or apoptosis of NSCs. CRISPR/dCas9-KRAB mediated knockdown of Lacuna gene expression leads to the opposite phenotype by inducing neuronal differentiation and suppressing Nestin+ and Olig2+ cells, again without any effect on proliferation or apoptosis of NSCs. Interestingly, despite the negative action of Lacuna on neurogenesis, its knockdown inhibits Eomes transcription, implying a simultaneous, but opposite, role in facilitating the Eomes gene expression. Collectively, our observations indicate a critical function of Lacuna in the gene regulation networks that fine tune the neuronal differentiation in the mammalian NSCs.

SUBMITTER: Ninou E

PROVIDER: S-EPMC8653915 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Long non-coding RNAs (lncRNAs) are master regulators of gene expression and have recently emerged as potential innovative therapeutic targets. The deregulation of lncRNA expression patterns has been associated with age-related and noncommunicable diseases in the bone tissue, including osteoporosis and tumors. However, the specific role of lncRNAs in physiological or pathological conditions in the bone tissue still needs to be further clarified, for their exploitation as therapeutic tools. In the present study, we evaluate the potential of the lncRNA CASC2 as a regulator of osteogenic differentiation and mineralization. Results show that CASC2 expression is decreased during osteogenic differentiation of human bone marrow-derived Mesenchymal Stem/Stromal cells (hMSCs). CASC2 knockdown, using small interfering RNA against CASC2 (siCASC2), increases the expression of the late osteogenic marker Bone Sialoprotein (BSP), but does not impact ALP staining level nor the expression of early osteogenic transcripts, including RUNX2 and OPG. Although siCASC2 does not impact hMSC proliferation nor apoptosis, it promotes the mineralization of hMSC cultured under osteogenic-inducing conditions, as shown by the increase of calcium deposits. Mass spectrometry-based proteomic analysis revealed that 89 proteins are regulated by CASC2 at late osteogenic stages, including proteins associated with bone diseases or anthropometric and musculoskeletal traits. Specifically, the Cartilage Oligomeric Matrix Protein (COMP) is highly enhanced by CASC2 knockdown at late stages of osteogenic differentiation, at both transcriptional and protein level. On the other hand, inhibition of COMP impairs osteoblasts mineralization as well as the expression of BSP. The results indicate that lncRNA CASC2 regulates late osteogenic differentiation and mineralization in hMSC via COMP and BSP. In conclusion, this study suggests that targeting lncRNA CASC2 could be a potential approach for modulating bone mineralization.

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Long Non-Coding RNA Lacuna Regulates Neuronal Differentiation of Neural Stem Cells During Brain Development.

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