Cilia in the choroid plexus: their roles in hydrocephalus and beyond

Abstract

Cilia are whip-like projections that are widely conserved in eukaryotes and function as a motile propeller and/or sensory platform to detect various extracellular stimuli. In vertebrates, cilia are ubiquitously found in most cells, showing structural and functional diversities depending on the cell type. In this review, we focus on the structure and function of cilia in choroid plexus epithelial cells (CPECs). CPECs form one or two dozen non-motile 9+0 cilia, which display transient acquisition of motility during development. Genetic malfunction of cilia can lead to failure of multiple organs including the brain. Especially, several groups have demonstrated that the defects in CPEC cilia cause the communicating form of hydrocephalus. In order to elucidate the molecular mechanisms underlying the hydrocephalus, we have previously demonstrated that the cilia possess an NPFF receptor for autocrine signaling to regulate transepithelial fluid transport. In this perspective, we also discuss the potential involvement of cilia in the other aspects of choroid plexus functions, such as the regulation of brain development and neuroinflammation.

Keywords: cerebrospinal fluid; cilia; diversity; hydrocephalus; multiciliogenesis.

Figure 1

General structure of cilia. (A) A longitudinal section of a CPEC cilium. The cilium emerges from the microvilli-rich apical cell surface. The structure is supported by the axoneme and basal body (pseudo-colored in green and magenta, respectively). The distal appendage (cyan) connects to the basal body and cell membrane. In the transition zone, characteristic Y-shaped structures bridges the axoneme and ciliary membrane, which can be recognized in horizontal sections. MTs, microtubules. Bar, 500 nm. (B) Schematics of transverse sections of motile 9+2 and non-motile 9+0 cilia.

Figure 2

Differences between CPEC and ependymal cilia. The formation of multiple cilia in CPECs occurs shortly after the cells differentiate from the neuroepithelium during organogenesis (about embryonic day 11 in mice). The cilia exhibit transient motility during the perinatal period, which peaks at the day of birth, and eventually become non-motile. However, ependyma undergo multiciliogenesis after birth to establish hundreds of motile cilia in 2 weeks. The beating orientation is aligned at both cellular and tissue levels by planar cell polarity signaling. In both cell types, multiciliogenesis is associated with the induction of transcription factors, FOXJ1 and RFX3. Ciliary localization of indicated molecules in neuroepithelium, choroid plexus epithelium, and ependyma are reported or implicated in Lehtinen et al. (2011), (Banizs et al., ; Wodarczyk et al., ; Narita et al., 2010), and Conductier et al. (2013), respectively. Knockout mice lacking general ciliogenesis genes, such as Ift88, Kif3a, and Bbs1,2,4, and 6, exhibit the communicating form of hydrocephalus. See text for details.