Expression Profiling of Solute Carrier Gene Families at the Blood-CSF Barrier

Abstract

The choroid plexus (CP) is a highly vascularized tissue in the brain ventricles and acts as the blood-cerebrospinal fluid (CSF) barrier (BCSFB). A main function of the CP is to secrete CSF, which is accomplished by active transport of small ions and water from the blood side to the CSF side. The CP also supplies the brain with certain nutrients, hormones, and metal ions, while removing metabolites and xenobiotics from the CSF. Numerous membrane transporters are expressed in the CP in order to facilitate the solute exchange between the blood and the CSF. The solute carrier (SLC) superfamily represents a major class of transporters in the CP that constitutes the molecular mechanisms for CP function. Recently, we systematically and quantitatively examined Slc gene expression in 20 anatomically comprehensive brain areas in the adult mouse brain using high-quality in situ hybridization data generated by the Allen Brain Atlas. Here we focus our analysis on Slc gene expression at the BCSFB using previously obtained data. Of the 252 Slc genes present in the mouse brain, 202 Slc genes were found at detectable levels in the CP. Unsupervised hierarchical cluster analysis showed that the CP Slc gene expression pattern is substantially different from the other 19 analyzed brain regions. The majority of the Slc genes in the CP are expressed at low to moderate levels, whereas 28 Slc genes are present in the CP at the highest levels. These highly expressed Slc genes encode transporters involved in CSF secretion, energy production, and transport of nutrients, hormones, neurotransmitters, sulfate, and metal ions. In this review, the functional characteristics and potential importance of these Slc transporters in the CP are discussed, with particular emphasis on their localization and physiological functions at the BCSFB.

Keywords: Allen Brain Atlas; BCSFB; CSF; Slc gene; blood-cerebrospinal fluid barrier; choroid plexus; solute carriers; transporters.

Figure 1

Distribution of expression profiles for Slc genes in the choroid plexus (CP). Of the 307 Slc genes analyzed in our ABA expression profiling study, 252 Slc genes were present in the mouse brain. The pie chart (A) shows percentage of these 252 Slc genes with expression categories based upon their average expression factor values (Ê) in the CP: “not detected” (E = 0); “low to moderate” (0 < E ≤ 9); “high” (9 < E ≤ 13); “very high” (13 < E ≤ 20). See Dahlin et al. (2009) for details regarding the definition and calculation of the E value. Panels in (B) show the restricted localization of Slc26a11 ISH signals in the CP (structure is indicated by the red boxes). The upper panel represents ISH image and the lower panel is the expression mask generated from the ISH image. In (C), a dendrogram of clustered brain regions (choroid plexus in red) is shown. Reproduced with permission from Dahlin et al. (American Society for Pharmacology and Experimental Therapeutics).

Figure 2

Localization of solute carrier (SLC) family transporters in the mammalian blood-CSF barrier/choroid plexus (CP) important for the production and secretion of CSF. Transporters colored in orange are discussed in details in this manuscript. Transporters known to play a role in ion transport at the BCSFB but are not discussed in this review are colored in white. Ion pumps and channels important in mammalian CP function are colored in blue. The suggested membrane localization of these transporters are based on in vitro, ex vivo, or in vivo studies using cells or tissues from various mammalian species as indicated (h, human; r, rat; m, mouse). Ions or substrates being transported by each transporter or channel are shown. Relatively well-established directionality of transport is shown by solid arrows while dashed arrows indicate potential directionality of transport. Transporters with unknown CP localization are listed along with their main substrates. Predicted localization of mitochondrial carriers is shown along with potential physiological substrates. CSF, cerebrospinal fluid.

Figure 3

Localization of solute carrier (SLC) family transporters in the mammalian blood-CSF barrier/choroid plexus (CP) suggested to have a role in nourishing the CP and the brain with amino acids, carbohydrates, fatty acids, vitamins, hormones, monoamines, sulfate, and metal ions. Transporters colored in orange are discussed in details in this manuscript. The suggested membrane localization of these transporters are based on in vitro, ex vivo, or in vivo studies using cells or tissues from various mammalian species as indicated (h, human; r, rat; m, mouse; p, porcine). Major classes or representatives of substrates for each transporter are shown (T3, triiodothyronine; rT3, reverse triiodothyronine; T4, thyroxine; MTX, methotrexate; OCs, organic cations). Relatively well-established directionality of transport is shown by solid arrows while dashed arrows indicate potential directionality of transport. Transporters with unknown CP localization are listed along with their main substrates. CSF, cerebrospinal fluid.