AGO1 in neural progenitor cells orchestrates brain development and sociability via LIN28A-REELIN axis

AGO1, an essential RNA binding protein (RBP) in RNA interference, is associated with autism spectrum disorder (ASD). However, the precise functions of AGO1 in brain development and related disorders remain largely unexplored. Here, we report the critical roles of AGO1 in neural progenitor cells (NPCs) in shaping the structure of the developing brain and promoting sociability. In human forebrain organoids, AGO1 KO disrupts the formation of ventricle-like structures and delays cortical layer development. We discovered that AGO1 KO results in a loss of polarity in NPCs, which subsequently reduces neuronal development. These AGO1 KO phenotypes originate from the failure to suppress LIN28A in NPCs. AGO1 is primarily localized in the nucleus within NPCs and binds to the LIN28A promoter region, thereby inhibiting LIN28A transcription. We found that increased LIN28A in AGO1 KO NPCs alters the expression of endoplasmic reticulum (ER)-associated genes. The aberrant polarity phenotype in AGO1 KO NPCs was successfully ameliorated by either LIN28A knockdown or supplementing critical candidate effectors. We observed the impaired cortical structure and hyposociability and an increased repetitive behavior in Ago1 knockout (KO) mouse, characteristic symptoms of ASD. Collectively, our findings elucidate the intricate molecular mechanisms orchestrated by nuclear AGO1 in NPCs and underscores its pivotal roles in brain development, providing significant insights into ASD.