IQSEC2 and ARF1 are involved in the development of the dentate gyrus

The IQ motif and SEC7 domain-containing protein 2 (IQSEC2) is a guanine nucleotide exchange factor (GEF) for ARF family small GTPases and is encoded by the IQSEC2 gene located on chromosome Xp11.22. More than 120 pathogenic variants in IQSEC2 have been identified in patients with neurodevelopmental disorders. In this study, we aimed to clarify the role of IQSEC2 during neonatal mouse dentate gyrus development using in vivo electroporation. Electroporation of a GFP expression vector together with a short hairpin RNA (shRNA) targeting IQSEC2 caused dentate granule neurons to stop at the boundary between the granule cell layer and the hilus (GCL/hilus). IQSEC2-deficient dentate granule cells exhibited increased distal dendritic complexity compared with control cells. IQSEC2 knockdown also reduced spine head diameter without affecting spine density. In contrast, exogenous IQSEC2 expression increased proximal dendritic complexity in neonatal dentate granule cells. We examined the ARF selectivity of IQSEC2 GEF activity and found that IQSEC2 activates ARF1, ARF3, and ARF6. Functional analyses revealed that ARF1 knockdown also confined dentate granule cells to the GCL/hilus region, which was consistent with the observation following IQSEC2 knockdown. In contrast, knockdown of ARF3 or ARF6 had no significant effect. Together, these results suggest that the IQSEC2 and ARF1 play a critical role in regulating neuronal positioning and dendritic development in the neonatal dentate gyrus.