Development of the choroid plexus and blood-CSF barrier

Abstract

Well-known as one of the main sources of cerebrospinal fluid (CSF), the choroid plexuses have been, and still remain, a relatively understudied tissue in neuroscience. The choroid plexus and CSF (along with the blood-brain barrier proper) are recognized to provide a robust protective effort for the brain: a physical barrier to impede entrance of toxic metabolites to the brain; a "biochemical" barrier that facilitates removal of moieties that circumvent this physical barrier; and buoyant physical protection by CSF itself. In addition, the choroid plexus-CSF system has been shown to be integral for normal brain development, central nervous system (CNS) homeostasis, and repair after disease and trauma. It has been suggested to provide a stem-cell like repository for neuronal and astrocyte glial cell progenitors. By far, the most widely recognized choroid plexus role is as the site of the blood-CSF barrier, controller of the internal CNS microenvironment. Mechanisms involved combine structural diffusion restraint from tight junctions between plexus epithelial cells (physical barrier) and specific exchange mechanisms across the interface (enzymatic barrier). The current hypothesis states that early in development this interface is functional and more specific than in the adult, with differences historically termed as "immaturity" actually correctly reflecting developmental specialization. The advanced knowledge of the choroid plexus-CSF system proves itself imperative to understand a range of neurological diseases, from those caused by plexus or CSF drainage dysfunction (e.g., hydrocephalus) to more complicated late-stage diseases (e.g., Alzheimer's) and failure of CNS regeneration. This review will focus on choroid plexus development, outlining how early specializations may be exploited clinically.

Keywords: blood-CSF barrier; brain patterning; cerebrospinal fluid; choroid plexus; development; epithelia; neuroependyma.

Figure 1

Location of choroid plexuses in the human brain. (A) The choroid plexuses are present in the two lateral, third and fourth ventricles (red ribbons). (B) Each of the plexuses is comprised of fenestrated vessels, with a single layer of intimately opposed choroid epithelial cells, joined by tight junctions—forming the blood- cerebrospinal fluid barrier. (C) Transmission electron micrographs of lateral ventricular choroid plexus. Stage I–the epithelial cells are pseudostratified with centrally located nuclei. Stage II/III–low columnar to cuboidal, basal-to-centrally located nuclei, with apical villi present (arrows, a characteristic from stage III onwards). Stage IV–cuboidal epithelial cells with central-to-apical nuclei and many villi (arrows). (C) reproduced from Ek et al. (2003) Copyright © 2003 Wiley All rights reserved. Abbreviations: BV, blood vessel; CP, choroid plexus; CPEC, choroid plexus epithelial cell; CSF, cerebrospinal fluid; LV, lateral ventricle; NU, nucleus; ST, stroma/basement membrane; TJ, tight junction; 3V, third ventricle.

Figure 2

Location of expression of transcription factors known to be important in plexus development and growth. The choroid plexus epithelial cells develop from modified neuroepithelium and are only added to the structure from the dorsal surface. No addition of cells is described from the ventral surface, and no transcription factors that promote differentiation into choroid plexus epithelium have been reported as expressed in this region. For full list of transcripts and references refer to Table 1. CSF, cerebrospinal fluid.

Figure 3

Schematic representation of transport pathways across the blood-cerebrospinal fluid barrier. The blood-cerebrospinal fluid (CSF) barrier is formed by tight junctions between neighboring choroid plexus epithelial cells—halting the paracellular movement of molecules both into, and out of, the brain. Additional chemical barriers exist to impede movement of molecules into the central nervous system. 1–Diffusion for hydrophilic molecules through a paracellular pathway is halted by tight junctions (TJ) between adjacent choroid plexus epithelial cells. 2–Efflux transporters (e.g., ABC family) actively remove specific (mostly) lipophilic solutes from cell cytoplasm and extracellular space. Though the majority of evidence suggests a basolateral removal of molecules to the blood space, there is some evidence that ABCB1 (PGP) and ABCG2 (BCRP) localize to the apical membrane of the choroid plexus (Rao et al., ; Gao and Meier, ; Gazzin et al., ; Niehof and Borlak, ; Ek et al., ; Reichel et al., 2011), however their function in this position is unknown. 3–Inward transporters (e.g., SLC family) actively transport ions, amino acids, and other small molecules across both basolateral and apical surfaces of plexus epithelial cells into the CSF. Without this active transport these molecules would be unable to cross the blood–CSF barriers as they are too hydrophilic and/or highly polarized. 4–Bi-directional transporters (e.g., OAT family). 5–Protein transporters (e.g., SPARC for albumin) specifically target individual proteins (or classes of protein) and transport them across the cells. 6–Vesicular transport/endocytosis due to presence of specific receptors (e.g., transthyretin receptor, TTR; insulin receptor, INSR) or non-specific mediators (e.g., vesicle-associated membrane proteins, VAMPs). 7–Bulk water flow from blood to CSF via aquaporin transporters, specifically AQP1 (Johansson et al., 2005).

Figure 4

Biondi ring tangles in aged human choroid plexus of the lateral and fourth choroid plexus. (A) Fluorescent light micrograph of thioflavin S-stained Biondi ring tangles (arrows) in the choroid plexus of the brain of a 78-year-old human female with Alzheimer's disease showing Biondi ring tangles appear as ring, tangle, serpentine, and curled profiles. (Magnification: 530×). (B) Scanning electron micrograph (Magnification 2500 ×) showing destruction of plexus epithelial cell containing ring-like Biondi inclusions. Arrow marks a ring bursting from an individual plexus epithelial cell. Material from 78 year old woman. (C) Electron micrograph of a choroid plexus from a 70-year-old male with Alzheimer's disease showing the fibrous Biondi ring tangles (one highlighted in pink, the other in green) associated with lipofuscin granules, mitochondria, and other cellular components. (Magnification: 10,300×). (A,C) Reproduced from Wen et al., Copyright © 1999 Elsevier Science B.V. All rights reserved. (B) Reproduced from (Kiktenko, 1986) Copyright © 1986 Springer All rights reserved. Abbreviations: BV, blood vessel; CPEC, choroid plexus epithelial cell; CSF, cerebrospinal fluid; N, nucleus.