Reelin Controls the Directional Orientation, Apical Localization and Length of Primary Cilia in Principal Neurons in the Cerebral Cortex

The primary cilia of pyramidal neurons in inside-out laminated regions orient predominantly toward the pial surface, reflecting reverse soma re-positioning during postnatal development. However, the mechanisms underlying the directional cilia orientation and reverse movement are unknown. Here we show that the primary cilia of pyramidal neurons are localized near the base of the apical dendrites and aligned on the nuclear side opposite to the axon initial segment. However, this pattern is not observed in atypical pyramidal neurons in the deep neocortex, excitatory neurons in non-laminated brain regions, interneurons, or astrocytes, where their cilia are irregularly positioned around the nuclei and lack preferred orientation. In Reelin-deficient mice ( reeler ), the directional orientation and apical localization of cilia in late-born neocortical and CA1 neurons are partially impaired, because their initial impairments are partially corrected during late postnatal development, along with a realignment of apical-basal orientation. In contrast, loss of Reelin drastically disrupts the directional orientation of primary cilia in early-born neocortical neurons and principal neurons in the piriform cortex; consistently, their cilia and centrioles do not preferably localize to the base of the apical dendrites. Additionally, Reelin deficiency increases the cilia length of principal neurons in the cerebral cortex after P14 when WT cilia stabilize, but not in interneurons, astrocytes, or excitatory neurons in non-laminated regions. Together, Reelin controls the directional orientation, intracellular localization, and length of primary cilia in principal neurons in the cerebral cortex. These results underscore primary cilia as a key apical unit, particularly prominent in late-born neurons.