A Circular RNA Expressed from the FAT3 Locus Regulates Neural Development

Sabine Seeler, Maria Schertz Andersen, Tamas Sztanka-Toth, Mateja Rybiczka-Tešulov, Marleen H. van den Munkhof, Chi Chih Chang, Muyesier Maimaitili, Morten Trillingsgaard Venø, Thomas Birkballe Hansen, R. Jeroen Pasterkamp, Agnieszka Rybak-Wolf, Mark Denham, Nikolaus Rajewsky, Lasse Sommer Kristensen*, Jørgen Kjems*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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 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.

Original languageEnglish
JournalMolecular Neurobiology
Volume60
Issue6
Pages (from-to)3239–3260
Number of pages22
ISSN0893-7648
DOIs
Publication statusPublished - Jun 2023

Keywords

  • Cerebral organoids
  • circFAT3
  • circRNAs
  • ncRNAs
  • Neural development
  • scRNA-seq

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