Evolving Roles of Primary Cilia in CNS Development and Neural Circuit Function: From Human Disease to Molecular Underpinnings

Primary cilia are small organelles acting as cellular antennae that sense and transduce diverse signals, including developmental signaling pathways in the developing central nervous system (CNS). This signaling is essential for normal CNS development, as evidenced by the prevalence of neurodevelopmental phenotypes in conditions arising from primary cilia dysfunction (ciliopathies). Though significant research has focused on the roles of primary cilia during CNS development, the functions of primary cilia in the mature CNS have only recently become a focus of investigation. Primary cilia are present on most vertebrate cells, including mature neurons and astrocytes and reportedly localize G-protein-coupled receptors, voltage-gated ion channels, and even synaptic proteins. Moreover, recent evidence highlights the dense "contactome" of cilia in the brain with adjacent neuronal structures and has even identified axo-ciliary synapses. Primary cilia are therefore both perfectly equipped and positioned to participate in regulating mature neural circuits. Consistent with these observations, primary cilia have also been linked to neurological and psychiatric symptoms without underlying brain malformations, both in ciliopathies and in nonciliopathy neurological conditions like autism spectrum disorder and schizophrenia. In this review, we bridge insights from human disease to evidence gained from animal and cell models to highlight the evolving roles of primary cilia in the developing and mature CNS. Primary cilia in the developing brain act as classical cellular antennae sensing secreted ligands, while primary cilia in the mature brain may also be capable of contact-dependent signaling, indicating a potential shift in the signaling capacity of primary cilia in the CNS.