TY - JOUR
T1 - A Circular RNA Expressed from the FAT3 Locus Regulates Neural Development
AU - Seeler, Sabine
AU - Andersen, Maria Schertz
AU - Sztanka-Toth, Tamas
AU - Rybiczka-Tešulov, Mateja
AU - van den Munkhof, Marleen H.
AU - Chang, Chi Chih
AU - Maimaitili, Muyesier
AU - Venø, Morten Trillingsgaard
AU - Hansen, Thomas Birkballe
AU - Pasterkamp, R. Jeroen
AU - Rybak-Wolf, Agnieszka
AU - Denham, Mark
AU - Rajewsky, Nikolaus
AU - Kristensen, Lasse Sommer
AU - Kjems, Jørgen
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
KW - Cerebral organoids
KW - circFAT3
KW - circRNAs
KW - ncRNAs
KW - Neural development
KW - scRNA-seq
UR - http://www.scopus.com/inward/record.url?scp=85148871374&partnerID=8YFLogxK
U2 - 10.1007/s12035-023-03253-7
DO - 10.1007/s12035-023-03253-7
M3 - Journal article
C2 - 36840844
AN - SCOPUS:85148871374
SN - 0893-7648
VL - 60
SP - 3239
EP - 3260
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 6
ER -