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

Abstract

The primary cilia of pyramidal neurons in inside-out laminated regions are oriented predominantly toward the pia, a pattern reflecting reverse soma movement during postnatal neurodevelopment. However, the mechanisms that regulate the directional cilia orientation remain unknown. Here we show that the primary cilia of neocortical pyramidal neurons are localized at the base of the apical dendrites and aligned distally and opposite to the axon initial segment (AIS). However, this pattern is not observed in atypical pyramidal neurons in the deep neocortex, excitatory neurons in non-laminated regions, or interneurons, where cilia are randomly positioned around the nuclei and lack preferred orientation. In Reelin-deficient mice (reeler), the directional orientation and apical location of cilia in late-born neocortical and CA1 neurons are altered. However, the initial impairments are partially corrected during early postnatal development. In contrast, Reelin deficiency disrupts the directional orientation and apical localization of primary cilia in early-born neocortical neurons and principal neurons in evolutionarily conserved laminated regions, where lack postnatal correction. Reelin deficiency also increases the cilia length in principal neurons across the cerebral cortex at a developmental stage when cilia length stabilizes in wild-type mice. In contrast, cilia elongation is not observed in interneurons, GFAP-positive astrocytes, or excitatory neurons in non-laminated reeler regions. Together, Reelin regulates the directional orientation, apical localization, and length of primary cilia in principal neurons in the cerebral cortex. This study underscores the cilium as a key apical domain, particularly prominent in late-born pyramidal neurons.