Heterotrimeric G-Protein, Gi1, Is Involved In The Regulation Of Proliferation, Neuronal Migration, And Dendrite Morphology During Cortical Development In Vivo

Heterotrimeric G-proteins are composed of alpha, beta, and gamma subunits, and function as signal transducers. Critical roles of the alpha-subunits of Gi/o family heterotrimeric G-proteins, G alpha i2, and G alpha o1, have so far been reported in brain development and neurodevelopmental disorders. In this study, we tried to clarify the role of G alpha i1, alpha-subunit of another Gi/o family member Gi1, during corticogenesis, based on the recent identification of its gene abnormalities in neurodevelopmental disorders. In western blot analyses, G alpha i1 was found to be expressed in mouse brain in a developmental stage-dependent manner. Morphological analyses revealed that G alpha i1 was broadly distributed in cerebral cortex with relatively high expression in the ventricular zone (VZ) at embryonic day (E) 14. Meanwhile, G alpha i1 was enriched in membrane area of yet unidentified early mitotic cells in the VZ and the marginal zone at E14. Acute knockdown of G alpha i1 within uteroelectroporation in cerebral cortex caused cell cycle elongation of the neural progenitor cells and promoted their cell cycle exit. G alpha i1-deficient cortical neurons also exhibited delayed radial migration during corticogenesis, with abnormally elongated leading processes and hampered nucleokinesis. In addition, silencing of G alpha i1 prevented basal dendrite development. The migration and dendritic phenotypes were at least partially rescued by an RNAi-resistant version of G alpha i1. Collectively, these results strongly suggest a crucial role of Gi1 in cortical development, and disturbance of its function may cause deficits in synaptic network formation, leading to neurodevelopmental disorders.