Emergence and Developmental Roles of the Cerebrospinal Fluid System

Abstract

We summarize recent work illuminating how cerebrospinal fluid (CSF) regulates brain function. More than a protective fluid cushion and sink for waste, the CSF is an integral CNS component with dynamic and diverse roles emerging in parallel with the developing CNS. This review examines the current understanding about early CSF and its maturation and roles during CNS development and discusses open questions in the field. We focus on developmental changes in the ventricular system and CSF sources (including neural progenitors and choroid plexus). We also discuss concepts related to the development of fluid dynamics including flow, perivascular transport, drainage, and barriers.

Figure 1:

The cerebral fluid environment changes in origin and composition over early development. A) Early cerebrospinal fluid (CSF) before choroid plexus (ChP) formation contains unique markers of brain parenchyma development, as well as some components that have been shown to signal to neural progenitors (black arrows). B) Later in development, CSF components can arise from the neural progenitors (black arrows), or from the ChP (green arrows), among other possible sources. CSF also mixes and flows to move components (blue arrow). CSF contents include free molecules (e.g. 5-HT; blocks), molecules bound to carrier proteins (e.g. RA+ Rbp4; ovals); organelle components (e.g. ribosomal or mitochondrial proteins), free proteins/peptides (e.g. Wnt3a; triangles, or cytokines; hexagons), or membrane-bound particles (e.g. exosomes; double-walled circles) containing proteins (e.g. Shh; green stars) or nucleic acid (e.g. miRNA; loops). These different components have unique signaling modalities including receptor binding to cells or fusion with cells in direct contact with CSF including neural progenitors (brown) or ChP (epithelial cells, green; mesenchymal cells, orange; endothelial cells, red; immune cells, purple; neurons, black). Developing brain schematized from mouse development.

Figure 2:

Development of the major components of the cerebral fluid system occurs across CNS developmental time. 1. After neural tube closure (E9 in mice; black dashed line) the brain ventricles form and develop. 2. Choroid plexus cells begin to emerge around E11 and the tissue continues maturing during the first postnatal weeks (Langford et al., 2020; Lun et al., 2015b). 3. Perivascular components begin to arise with endothelial tight junctions appearing around E12 and maturation of barrier function beginning at E15.5 (O’Brown et al., 2018). Maturation and polarization of perivascular astrocytes required for glymphatic function occurs around E18/birth (Munk et al., 2019). 4. Ependymal cells are generated by radial glia beginning at E14 and then become postmitotic (Spassky et al., 2005). 5. Meningeal lymphatic vessels sprout from existing vessels at the base of the skull around E18/birth in mice and this system continues mature throughout the first postnatal month (Antila et al., 2017). Developing brain schematized from mouse development.