Developmental changes in the transcriptome of the rat choroid plexus in relation to neuroprotection

Abstract

BackgroundThe choroid plexuses are the interface between the blood and the cerebrospinal fluid (CSF) contained within the ventricular spaces of the central nervous system. The tight junctions linking adjacent cells of the choroidal epithelium create a physical barrier to paracellular movement of molecules. Multispecific efflux transporters as well as drug-metabolizing and antioxidant enzymes functioning in these cells contribute to a metabolic barrier. These barrier properties reflect a neuroprotective function of the choroid plexus. The choroid plexuses develop early during embryogenesis and provide pivotal control of the internal environment throughout development when the brain is especially vulnerable to toxic insults. Perinatal injuries like hypoxia and trauma, and exposure to drugs or toxic xenobiotics can have serious consequences on neurogenesis and long-term development. The present study describes the developmental expression pattern of genes involved in the neuroprotective functions of the blood–CSF barrier.MethodsThe transcriptome of rat lateral ventricular choroid plexuses isolated from fifteen-day-old embryos, nineteen-day old fetuses, two-day old pups, and adults was analyzed by a combination of Affymetrix microarrays, Illumina RNA-Sequencing, and quantitative RT-PCR.ResultsGenes coding for proteins involved in junction formation are expressed early during development. Overall perinatal expression levels of genes involved in drug metabolism and antioxidant mechanisms are similar to, or higher than levels measured in adults. A similar developmental pattern was observed for multispecific efflux transporter genes of the Abc and Slc superfamilies. Expression of all these genes was more variable in choroid plexus from fifteen-day-old embryos. A large panel of transcription factors involved in the xenobiotic- or cell stress-mediated induction of detoxifying enzymes and transporters is also expressed throughout development.ConclusionsThis transcriptomic analysis suggests relatively well–established neuroprotective mechanisms at the blood-CSF barrier throughout development of the rat. The expression of many transcription factors early in development raises the possibility of additional protection for the vulnerable developing brain, should the fetus or newborn be exposed to drugs or other xenobiotics.

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…This is in line with an early maturation of the choroid plexuses during development and suggests that the BCSFB plays a predominant role in brain protection in the neonate and young infant [73,150].…”

“…Further protection is provided by antioxidant enzymes (catalase, superoxide dismutase SOD, glutathione peroxidases GPx) and by epoxide hydrolase, which inactivate reactive oxygen species and reactive pro-oxidant epoxides, respectively ◂ depresses ABCC1 levels, which may actually potentiate bilirubin neurotoxicity [45]. Of importance, cytoprotective transporters and enzymes are under the transcriptional regulation of nuclear factors, which are expressed in the choroid plexuses [73]. The nuclear factor erythroid 2-related factor 2 pathway, in particular, represents an attractive target to protect the BCSFB and induce its antioxidant capacities in neurological disorders associated with oxidative stress [168].…”

Functional and Genetic Analysis of Choroid Plexus Development in Zebrafish

“…In a recent study, mmp9 was suggested to lead to Cldn5 degradation at the BCSFB allowing for leukocytes entry into the CSF (Chiu and Lai, 2013). mmp9 is also said to be up-regulated in the CP in the presence of inflammation (Kratzer et al, 2013). We observed a significant increase in mmp9 expression in cp27.5 mutants; however, whether up-regulation is specific to the BCSFB requires further investigation.…”

“…Pleiotropy is where a mutation in one gene can cause multiple phenotypes (Lobo, 2008) Recent discoveries have shed light on the importance of the CP and its contribution to disease. For example, transcriptome analysis during early development revealed that the CP expresses numerous genes essential for CP function, including those for tight junctions, transporters, and metabolic function (Liddelow et al, 2012), protecting the brain from potentially harmful insults (Kratzer et al, 2013). The mutants identified in our study will be used to identify genes essential for maintaining epithelial barrier integrity as well as genes essential for initial barrier formation.…”

Differences in the molecular structure of the blood-brain barrier in the cerebral cortex and white matter: an in silico, in vitro, and ex vivo study

“…ABC transporters characteristic to BBB endothelial cells (ABCB1/ MDR1/P-gp, ABCG2/BCRP, ABCA2, and ABCA8) were included in cluster 5, while members of the ABCC family expressed both by brain endothelial cells and epithelial cells of the choroid plexus (19,40) appeared in clusters 1-3. The main SLC transporters of the BBB were clustered in clusters 1, 2, and 4.…”