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Development and functions of the choroid plexus–cerebrospinal fluid system

Key Points

  • The choroid plexus (ChP) is a secretory tissue found in each of the brain ventricles, the main function of which is to produce cerebrospinal fluid (CSF). Although the ChP–CSF system is essential for proper development of the nervous system owing to fluid pressure within the ventricles as well as myriad CSF-borne signalling factors, it is nevertheless one of the most understudied areas of neurobiology.

  • A highly organized tissue, the ChP consists of simple cuboidal epithelial cells surrounding a core of fenestrated capillaries and connective tissue. As the interface between peripheral circulation and the CNS, the ChP forms the blood–CSF barrier via tight junctions between adjacent epithelial cells to restrict free passage of solutes from blood into CSF, and vice versa.

  • The ChP is present in chordates above the lancelet, and its development, which is classically categorized into four stages on the basis of its histological appearance, occurs in a stereotyped manner. Further, the order of ChP development seems to be conserved across species, with the hindbrain (fourth ventricle) ChP appearing first, followed by the bilateral appearance of the telencephalic (lateral ventricle) ChP, and the diencephalic (third ventricle) ChP appearing last.

  • The cell-intrinsic and -extrinsic molecular mechanisms that regulate ChP development are just now being elucidated. Although ChP epithelial cells are derived from neuroepithelial progenitors, they are non-neural cells in their mature state, suggesting the need to suppress neural character in favour of a non-neural cell fate.

  • Genetic fate-mapping studies have illustrated that cells contributing to the telencephalic ChP and hindbrain ChP exhibit lineage segregation in the mature tissues. Moreover, the ChPs are transcriptionally heterogeneous, a trait that appears to be evolutionarily conserved from mice to humans.

  • Recent work in the field has identified several ChP-derived factors with important roles in the developing and adult brain. Importantly, the ChP epithelial cell secretome has been described, suggesting a role for a ventricle-specific, regionalized CSF in the developing brain.

Abstract

The choroid plexus (ChP) is the principal source of cerebrospinal fluid (CSF), which has accepted roles as a fluid cushion and a sink for nervous system waste in vertebrates. Various animal models have provided insights into how the ChP–CSF system develops and matures. In addition, recent studies have uncovered new, active roles for this dynamic system in the regulation of neural stem cells, critical periods and the overall health of the nervous system. Together, these findings have brought about a paradigm shift in our understanding of brain development and health, and have stimulated new initiatives for the treatment of neurological disease.

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Figure 1: The choroid plexus–cerebrospinal fluid system.
Figure 2: Progenitor domains of the hindbrain and telencephalic choroid plexi.
Figure 3: Morphological stages of the developing choroid plexus epithelium.
Figure 4: Telencephalic and hindbrain choroid plexi are transcriptionally and functionally distinct tissues.

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Acknowledgements

The authors thank members of the Lehtinen and Monuki laboratories for helpful discussions. The authors apologize to investigators whose work they could not reference owing to space limitations. This work was supported by CIRM RN2-00915-1 and UCI ICTS and ADRC Pilot Project Awards (to E.S.M.); and Pediatric Hydrocephalus Foundation, Alfred P. Sloan Foundation, NIH K99/R00 NS072192 and R01 NS088566 (to M.K.L.).

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Glossary

Cribriform plate

The region of skull bone supporting the olfactory bulbs, which is perforated to allow the passage of olfactory nerves from the nasal cavities.

Hydrocephalus

A condition resulting from excess accumulation of cerebrospinal fluid within the ventricles of the brain.

Neuroepithelial cells

The stem cells of the nervous system, these cells initially undergo symmetric division early in development to expand the progenitor cell pool, and subsequently give rise to more lineage-restricted cells at the start of neurogenesis, including radial glial and choroid plexus epithelial cells.

Rhombic lip

A transient structure located at the interface between the roof plate and dorsal neuroepithelium, which functions as a germinal epithelium and a source of diffusible signals.

Cortical hem

A signalling centre located bilaterally near the telencephalic midline, which functions as a source of WNTs and bone morphogenetic proteins for cerebral cortical, hippocampal and choroid plexus development, as well as a source of Cajal–Retzius cells.

Prosomeres

Segments of the anterior neural tube early in embryonic development that give rise to forebrain structures.

Rhombomeres

Transient, regularly spaced repeating units of hindbrain cells in the developing embryo that will ultimately give rise to the rhombencephalon.

Trisomy 18

A genetic condition in which cells contain three copies of chromosome 18 rather than the normal two. It is also known as Edwards syndrome.

Aicardi syndrome

A developmental disorder that is characterized by infantile spasms and defects of the corpus callosum and eyes (chorioretinopathy); see Online Mendelian Inheritance in Man 304050.

Bromodeoxyuridine

(BrdU). A synthetic thymidine analogue that can be incorporated into replicating DNA.

Choroid plaque

The non-papillary tissue at the immediate dorsal midline that separates the two choroid plexi of the lateral ventricles.

Fenestrated capillaries

Openings in the endothelium are bridged by thin diaphragms permeable to water and small molecules.

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Lun, M., Monuki, E. & Lehtinen, M. Development and functions of the choroid plexus–cerebrospinal fluid system. Nat Rev Neurosci 16, 445–457 (2015). https://doi.org/10.1038/nrn3921

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