Primate-specific microRNA-1202 regulates dopaminergic neurogenesis by targeting APC2 and modulates WNT/β-catenin signaling pathway in midbrain organoid

Abstract

MicroRNAs (miRNAs) are generally evolutionarily conserved, but a small number of them are found exclusively in primates. MiR-1202 is a primate-specific miRNA that was previously revealed as being involved in major depression disorder (MDD). Moreover, the genomic locus where miR-1202 locates (6q25.3) is strongly associated with recurrent early-onset MDD and neurodevelopmental disorder. We hypothesize that miR-1202 plays a unique role in the brain in fine-tuning the transcriptional network that governs neurogenesis. Here, we reported that microdeletion of miR-1202 resulted in retarded organoid growth but enhanced dopaminergic (DA) neuron differentiation in midbrain organoids. Integrated analysis of miRNA-interacting targets and transcriptional changes in miR-1202 knockout cells revealed that APC2, a negative regulator of canonical WNT/{beta}-catenin pathway, was a downstream target of miR-1202. Knockdown of APC2 resulted in attenuated DA neurogenesis, in contrast to the enhanced DA neurogenesis in miR-1202 knockout cells. Treatments of the brain organoids with antidepressants increased miR-1202 expression and simultaneously inhibited APC2 expression. Consistently, APC2 expression was found to increase in MDD patients. Our results suggest that miR-1202 regulates dopamine neurogenesis by inhibiting the APC2/WNT signaling pathway, which plays a distinct role in the midbrain-hindbrain regional patterning during the early development of the central nervous system.