The Diversified Astrocyte Developmental Programs are Modulated by Primary Ciliary Signaling

Astrocyte diversity is greatly influenced by local environmental modulation. Here, we report that the vast majority of brain astrocytes across the entire brain possess a singular primary cilium, a specialized signaling antenna localized to cell soma. Comparative single-cell transcriptomics reveals that primary cilia mediate canonical Shh signaling to modulate astrocyte subtype-specific core features in synaptic regulation, intracellular transport, energy and metabolism. Independent of canonical Shh signaling, primary cilia are important regulators for astrocyte morphology and intracellular signaling balance. Dendritic spine analysis and transcriptomics reveal that perturbation of astrocytic cilia leads to disruption of neuronal development and global intercellular connectomes in the brain. Ultimately, mice with primary ciliary deficient astrocytes show behavioral deficits in sensorimotor function, sociability, learning and memory. Our results uncover a critical role for primary cilia in transmitting local cues that drive the region-specific diversification of astrocytes within the developing brain.