A Circular RNA Expressed from the FAT3 Locus Regulates Neural Development
Seeler, Sabine; Andersen, Maria Schertz; Sztanka-Toth, Tamas; Rybiczka-Tešulov, Mateja; van den Munkhof, Marleen H.; Chang, Chi Chih; Maimaitili, Muyesier; Venø, Morten Trillingsgaard; Hansen, Thomas Birkballe; Pasterkamp, R. Jeroen; Rybak-Wolf, Agnieszka; Denham, Mark; Rajewsky, Nikolaus; Kristensen, Lasse Sommer; Kjems, Jørgen
(2023) Molecular Neurobiology, volume 60, issue 6, pp. 3239 - 3260
(Article)
Abstract
Circular RNAs (circRNAs) are key regulators of cellular processes, are abundant in the nervous system, and have putative regulatory roles during neural differentiation. However, the knowledge about circRNA functions in brain development is limited. Here, using RNA-sequencing, we show that circRNA levels increased substantially over the course of differentiation of
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human embryonic stem cells into rostral and caudal neural progenitor cells (NPCs), including three of the most abundant circRNAs, ciRS-7, circRMST, and circFAT3. Knockdown of circFAT3 during early neural differentiation resulted in minor transcriptional alterations in bulk RNA analysis. However, single-cell transcriptomics of 30 and 90 days differentiated cerebral organoids deficient in circFAT3 showed a loss of telencephalic radial glial cells and mature cortical neurons, respectively. Furthermore, non-telencephalic NPCs in cerebral organoids showed changes in the expression of genes involved in neural differentiation and migration, including FAT4, ERBB4, UNC5C, and DCC. In vivo depletion of circFat3 in mouse prefrontal cortex using in utero electroporation led to alterations in the positioning of the electroporated cells within the neocortex. Overall, these findings suggest a conserved role for circFAT3 in neural development involving the formation of anterior cell types, neuronal differentiation, or migration.
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Keywords: Cerebral organoids, circFAT3, circRNAs, ncRNAs, Neural development, scRNA-seq, Neurology, Cellular and Molecular Neuroscience
ISSN: 0893-7648
Publisher: Humana Press
Note: Funding Information: This work was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (grant no. 721890-circRTrain), the Villum Foundation (grant no. 13393), the Carlsberg Foundation (grant no. CF16-0087), and Lundbeckfonden (grant no. DANDRITE- R248-2016–2518). Funding Information: The authors acknowledge AU Health Bioimaging Core Facility for the use of equipment and support of the imaging facility. Library preparation and Quantseq 3’end sequencing were performed by the NGS Core Centre, Department of Molecular Medicine, Aarhus University Hospital, Denmark. Cell sorting was performed at the FACS Core Facility, Aarhus University, Denmark. We thank Prof. Anders Nykjær and Dr. Peter Lund Ovesen for providing antibodies. We thank Ruth Pareja for technical support with the human cerebral organoid cultures. The authors thank Salah Ayoub and Anastasiya Boltengagen for the support in performing sequencing runs. We thank Dr. Anne Færch Nielsen for critical input and reading of the manuscript. In addition, we thank M.D., R.J.P., N.R., L.S.K., and J.K. lab members for valuable discussions and critical feedback. Publisher Copyright: © 2023, The Author(s).
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