Abstract
Adult brain is protected from entry of drugs and toxins by specific mechanisms such as ABC (ATP-binding Cassette) efflux transporters. Little is known when these appear in human brain during development. Cellular distribution of three main ABC transporters (ABCC1, ABCG2, ABCB1) was determined at blood-brain barriers and interfaces in human embryos and fetuses in first half of gestation. Antibodies against claudin-5 and -11 and antibodies to α-fetoprotein were used to describe morphological and functional aspects of brain barriers. First exchange interfaces to be established, probably at 4–5 weeks post conception, are between brain and embryonic cerebrospinal fluid (eCSF) and between outer surface of brain anlage and primary meninx. They already exclude α-fetoprotein and are immunopositive for both claudins, ABCC1 and ABCG2. ABCB1 is detectable within a week of blood vessels first penetrating into brain parenchyma (6–7 weeks post conception). ABCC1, ABCB1 and ABCG2 are present at blood-CSF barrier in all choroid plexuses from first appearance (7 weeks post conception). Outer CSF-brain interfaces are established between 9–11 weeks post conception exhibiting immunoreactivity for all three transporters. Results provide evidence for sequential establishment of brain exchange interfaces and spatial and temporal timetable for three main ABC transporters in early human brain.
Highlights
An important feature of the developing brain is that it is separated from the general internal environment of the embryo and fetus by a complex series of interfaces composed of morphological structures, cellular transporters and various channels in cell membranes of each interface
Adult brain is separated from the periphery by a set of morphological and physiological mechanisms that are present at various interfaces between the brain parenchyma and surrounding fluids
Limiting entry of potential neurotoxins to the brain is an essential function of brain barrier mechanisms, both during development and in the adult brain
Summary
An important feature of the developing brain is that it is separated from the general internal environment of the embryo and fetus by a complex series of interfaces composed of morphological structures, cellular transporters and various channels in cell membranes of each interface. Circumferential tight junctions sealing the intercellular space between cells of the interfaces create barriers with a diffusion restraint for lipid insoluble molecules This diffusion restraint allows cellular transport mechanisms in the barrier to be established to provide the functional mechanisms that control the internal environment of the brain. In this study we report on the immunohistochemically defined spatial and temporal distribution of three key ABC transporters (ABCB1, ABCC1, ABCG2) in human embryonic and fetal brain We describe their emergence and in some cases decline in the barrier interfaces of the developing human brain from the period of development before vascularization of the brain (i.e. before the advent of the blood-brain barrier itself), through the first appearance of the choroid plexuses, the first stages of CSF secretion and differentiation of the outer meningeal interfaces with subsequent establishment of the subarachnoid space
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