Title:

Neuronal primary cilia regulate postnatal pyramidal cell positioning to the deep and superficial sublayers in the mouse cerebral cortex

It is well-recognized that primary cilia regulate embryonic neurodevelopment, but little is known about their roles during postnatal neurodevelopment. The hippocampal striatum pyramidal (SP) is subdivided into deep and superficial sublayers and gradually condensed into a compact lamina in the first postnatal two weeks, whereas simultaneously the volume of the neocortex greatly expands. It is elusive how pyramidal neurons position to two cortical sublayers postnatally. Here, we show that the axonemes of primary cilia in the deep and superficial sublayers of hippocampal SP point in the opposite directions, while neuronal cilia in neocortical sublayers display the same orientation. Neuronal primary cilia in the CA1 SP undergo marked changes in morphology and orientation from postnatal day 5 (P5) to P14, concurrent with cell positioning to two sublayers and with neural maturation. Surprisingly, the centrioles of late-born neurons migrate excessively to cluster at SP bottom before cilia protrusion and a reverse movement back to the main plate. Similarly, this “pull-back” movement is also identified on late-born cortical pyramidal neurons. We further reveal that ablation of neuronal cilia selectively in the mouse forebrain leads to significantly megalencephaly, increased superficial neurons positioned in the deep sublayer of the neocortex and gyrification in mouse brain during the early postnatal stage. Transgenic overexpression of Arl13B, a protein regulating ciliogenesis, not only elongates primary cilia and promotes earlier cilia protrusion, but also decreases the brain size after P14. Together, this study provides the first evidence that primary cilia regulate brain structure and size, pyramidal neuronal positioning in the mouse cortex and late-born pyramidal neurons undergo a reverse movement for cell positioning.

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