Embryonic cerebrospinal fluid formation and regulation.

The vertebrate brain is organized, from its embryonic origin and throughout adult life, around a dynamic and complex fluid, the cerebrospinal fluid (CSF). There is growing interest in the composition, dynamics and function of the CSF in brain development research. It has been demonstrated in higher vertebrates that CSF has key functions in delivering diffusible signals and nutrients to the developing brain, contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the patterning of the brain. It has also been shown that the composition and the homeostasis of CSF are tightly regulated following the closure of the anterior neuropore, just before the initiation of primary neurogenesis in the neural tissue surrounding brain cavities, before the formation of functional choroid plexus. In this review we draw together existing literature about the composition and formation of embryonic cerebrospinal fluid in birds and mammals, from the closure of the anterior neuropore to the formation of functional fetal choroid plexus, including mechanisms regulating its composition and homeostasis. The significance of CSF regulation within embryonic brain is also discussed from an evolutionary perspective.

The embryonic blood-cerebrospinal fluid barrier function before the formation of the fetal choroid plexus: role in cerebrospinal fluid formation and homeostasis.

Cerebrospinal fluid (CSF) has attracted interest as an active signaling milieu that regulates brain development, homeostasis, and course disease. CSF is a nutrient-rich fluid, which also contains growth factors and signaling molecules that regulate multiple cell functions in the central nervous system (CNS). CSF constitution is controlled tightly and constituent concentrations are maintained narrow, depending on developmental stage. From fetal stages to adult life, CSF is produced mainly by the choroid plexus. The development and functional activities of the choroid plexus, and other blood-brain barrier systems in adults, have been extensively analyzed. However, the study of CSF production and homeostasis in embryos from the closure of the anterior neuropore, when the brain cavities become physiologically sealed, to the formation of the functional fetal choroid plexus has been largely neglected. This developmental stage is characterized by tightly controlled morphological and cellular events in the anterior part of the CNS, such as rapid brain anlagen growth and initiation of primary neurogenesis in the neural progenitor cells lining the cavities, events which are driven by specific molecules contained within the embryonic CSF. In this article, we review the existing literature on formation and function of the temporary embryonic blood-CSF barrier, from closure of the anterior neuropore to the formation of functional fetal choroid plexuses, with regard to crucial roles that embryonic CSF plays in neural development.

The embryonic blood-CSF barrier has molecular elements to control E-CSF osmolarity during early CNS development.

In vertebrates, brain development takes place at the expanded anterior end of the neural tube. After closure of the anterior neuropore, the brain wall forms a physiologically sealed cavity that encloses embryonic cerebrospinal fluid (E-CSF), a complex and protein-rich fluid. E-CSF has several crucial roles in brain anlagen development. In this respect, during the initiation of neurogenesis, increases in the volume of brain cavities account for 70% of the total growth of the brain primordium, and are accompanied by a parallel increase in E-CSF volume. Recently, we reported the presence of several blood vessels located in the brain stem lateral to the ventral midline, at the mesencephalon and prosencephalon level, which have a transient blood-CSF barrier function in chick embryos by transporting proteins in a selective manner via transcellular routes. These blood vessels control E-CSF protein composition and homeostasis during this early stage of CNS development, just after closure of the neuropores. Here we report that in chick and rat embryos these same blood vessels, which lie close to the neuroectoderm, express several molecules related to water and ion transport, namely AQP1, AQP4 and Kir4.1. Our results confirm that a blood-CSF barrier controls E-CSF composition and homeostasis from early stages of brain development in chick embryos, including water and ion influx, thus regulating E-CSF osmolarity. On the basis of our findings, we also propose that a similar blood-CSF barrier is present in mammals at equivalent developmental stages of the brain.

A blood-CSF barrier function controls embryonic CSF protein composition and homeostasis during early CNS development.

In vertebrates, early brain development takes place at the expanded anterior end of the neural tube, which is filled with embryonic cerebrospinal fluid (E-CSF). Most of the proteins contained within the E-CSF, which play crucial roles in CNS development, are transferred from the blood serum. Two important questions are how E-CSF is manufactured and how its homeostasis is controlled. In this respect, the timing of the blood-CSF barrier formation is controversial. Recently, the concept of a functional dynamic barrier has been introduced. This type of barrier is different from that found in adults and is adapted to the specific requirements and environment of the developing nervous system. In this study, we injected a number of proteins into the outflow of the heart and into the cephalic cavities and examined their transport rate between these two embryo compartments. The results indicated that a functional blood-CSF barrier dynamically controls E-CSF protein composition and homeostasis in chick embryos before the formation of functional choroid plexuses. We also showed that proteins are transferred through transcellular routes in a specific area of the brain stem, close to the ventral mesencephalic and prosencephalic neuroectoderm, lateral to the ventral midline, in particular blood vessels. This study contributes to our understanding of the mechanisms involved in CNS development, as this blood-CSF interface regulates the composition of E-CSF by regulating its specific composition.

Embryonic blood-cerebrospinal fluid barrier formation and function.

During embryonic development and adult life, brain cavities and ventricles are filled with cerebrospinal fluid (CSF). CSF has attracted interest as an active signaling medium that regulates brain development, homeostasis and disease. CSF is a complex protein-rich fluid containing growth factors and signaling molecules that regulate multiple cell functions in the central nervous system (CNS). The composition and substance concentrations of CSF are tightly controlled. In recent years, it has been demonstrated that embryonic CSF (eCSF) has a key function as a fluid pathway for delivering diffusible signals to the developing brain, thus contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the expansion and patterning of the brain. From fetal stages through to adult life, CSF is primarily produced by the choroid plexus. The development and functional activities of the choroid plexus and other blood-brain barrier (BBB) systems in adults and fetuses have been extensively analyzed. However, eCSF production and control of its homeostasis in embryos, from the closure of the anterior neuropore when the brain cavities become physiologically sealed, to the formation of the functional fetal choroid plexus, has not been studied in as much depth and remains open to debate. This review brings together the existing literature, some of which is based on experiments conducted by our research group, concerning the formation and function of a temporary embryonic blood-CSF barrier in the context of the crucial roles played by the molecules in eCSF.

Homeostasis of cerebrospinal fluid has a role in early brain development.

Embryonic cerebrospinal fluid (E-CSF) is a protein-containing fluid present in brain cavities that plays key roles in neuronal development and function. From the beginning of primary brain neurogenesis, E-CSF composition and homeostasis are precisely tuned by a transient blood-CSF barrier function, which controls protein transport and their relative concentration of within-brain cavities. One of the proteins found in E-CSF is ovalbumin, which is postulated to play a role in nutrition. Here, we address the question of whether neuroepithelial progenitor cells in developing chick embryos use ovalbumin as a highly specific nutritional source of amino acids or alternatively whether they use other amino acid sources, despite the fact that they cannot be transported from blood serum to brain cavities under physiological conditions. Although ovalbumin was not found to be a key protein required for neurogenesis and cell survival, our observations reinforce the crucial role of the embryonic blood-CSF barrier, as its precise regulation of protein transport and E-CSF homeostasis ensures the maximum efficiency of neural development.