Mouse multidrug resistance 1a/3 gene is the earliest known endothelial cell differentiation marker during blood‐brain barrier development

Qin, Ying; Sato, Thomas N.

doi:10.1002/aja.1002020209

Cited by 73 publications

(28 citation statements)

References 29 publications

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“…In mice and humans, P-gp expression is an early marker of blood-brain barrier development (Qin and Sato, 1995;Schumacher and Mollgard, 1997). In a previous report, antibody C219-detectable P-gp was 5-fold higher in the brains of adult FVB mice compared with newborn mice Tsai et al, 2002).…”

Section: Discussionmentioning

confidence: 88%

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OFMDR1AEXPRESSION

Goralski

Acott²,

Fraser³

et al. 2005

Drug Metab Dispos

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Section: Discussionmentioning

confidence: 88%

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OFMDR1AEXPRESSION

Goralski

Acott²,

Fraser³

et al. 2005

Drug Metab Dispos

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“…This is of some interest as components of the Wnt signalling pathway are present in the developing brain blood vessels at the stage at which one of these transporters i.e. p-gp is known to appear (Qin and Sato 1995). This multidrug efflux ABC transporter plays a major role in protection at the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

“…The idea that Wnt signalling pathways may also influence the barrier properties of blood vessels has not yet been addressed. It is interesting to note however that Wnt signalling in blood vessels in the brain during development (Maretto et al 2003) appears with the same time frame as appearance of the efflux transporter, p-glycoprotein (p-gp) (ABCB1) in the brain vasculature (Qin and Sato 1995). p-gp plays an important role at the blood-brain barrier in preventing access of unwanted substances to the brain (Schinkel 1999).…”

mentioning

confidence: 99%

Activation of β‐catenin signalling by GSK‐3 inhibition increases p‐glycoprotein expression in brain endothelial cells

Lim

Kania

Wijesuriya

et al. 2008

Journal of Neurochemistry

144

114

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This study investigates involvement of β-catenin signalling in regulation of p-glycoprotein (p-gp) expression in endothelial cells derived from brain vasculature. Pharmacological interventions that enhance or that block β-catenin signalling were applied to primary rat brain endothelial cells and to immortalized human brain endothelial cells, hCMEC/D3, nuclear translocation of β-catenin being determined by immunocytochemistry and by western blot analysis to confirm effectiveness of the manipulations. Using the specific glycogen synthase kinase-3 (GSK-3) inhibitor 6-bromoindirubin-3′-oxime enhanced β-catenin and increased p-gp expression including activating the MDR1 promoter. These increases were accompanied by increases in p-gp-mediated efflux capability as observed from alterations in intracellular fluorescent calcein accumulation detected by flow cytometry. Similar increases in p-gp expression were noted with other GSK-3 inhibitors, i.e. 1-azakenpaullone or LiCl. Application of Wnt agonist [2-amino-4-(3,4-(methylenedioxy) benzylamino)-6-(3-methoxyphenyl)pyrimidine] also enhanced β-catenin and increased transcript and protein levels of p-gp. By contrast, down-regulating the pathway using Dickkopf-1 or quercetin decreased p-gp expression. Similar changes were observed with multidrug resistance protein 4 and breast cancer resistance protein, both known to be present at the blood-brain barrier. Supplementary materialThe following supplementary material is available for this article: Table S1 Primers used in the polymerase chain reaction. This material is available as part of the online article from: http://www.blackwell-synergy.com/doi/abs/10.1111/j. 1471-4159.2008.05537.x. (This link will take you to the article abstract). Please note: Blackwell Publishing is not responsible for the content or functionality of any supplementary materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. Europe PMC Funders GroupAuthor Manuscript J Neurochem. Author manuscript; available in PMC 2015 January 23. et al. 2004). In this signalling pathway, interactions of Wnt proteins with the cell surface Frizzled receptors and associated membrane proteins lead to inactivation of glycogen synthase kinase-3 (GSK-3), resulting in stabilization of β-catenin. As a result, free β-catenin is allowed to accumulate and be translocated to the nucleus, binding to the transcription factor Tcf/Lef to alter the expression of target genes (Logan and Nusse 2004). Wnt proteins can also activate non-canonical pathways that do not involve β-catenin.There is evidence that Wnt signalling, particularly via the canonical pathway plays a role in vascular endothelial survival and proliferation (Wright et al. 1999;Masckauchan et al. 2005). Wnt ligands and Wnt ligand receptors have been identified in different types of vascular endothelial cells (Goodwin et al. 2006). Interactions between canonical and noncanonical pathways may be such that the one then modulates the ...

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“…Little is known regarding the ontogeny of Pgp expression in the brain and published data provide conflicting results regarding Pgp BBB expression in the perinatal period. Immunohistochemical studies in humans and mice suggest that Pgp is expressed during embryogenesis [13,14] in brain microvessels and may be an early marker of BBB development. Other investigators have failed to detect Pgp expression in brain microvessels until postnatal time periods [15].…”

Section: Introductionmentioning

confidence: 99%

P-Glycoprotein Expression in Mouse Brain Increases with Maturation

et al. 2002

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The mdr1a isoform of P-glycoprotein (Pgp) is an integral plasma membrane efflux pump expressed in adult brain capillary endothelial cells and astrocytes of the blood-brain barrier. We determined the developmental pattern of Pgp expression in brain tissue at embryonic day 16 (E16), day of life 0 (D0), day of life 7 (D7), day of life 21 (D21), and adults (Ad). The relative expression of Pgp mRNA and protein was indexed as a percent (mean ± SEM) of D0 levels. Pgp mRNA levels increased significantly (p < 0.01) with maturation (E16: 75 ± 8%; D21: 303 ± 37%, and Ad: 1,160 ± 120%). Similarly, Pgp protein expression was observed at E16 and increased significantly (p < 0.01) during development (E16: 52 ± 8%; D7: 187 ± 23%; D21: 440 ± 48%, and Ad: 441 ± 56%). This developmental pattern of enhanced blood-brain barrier Pgp expression with maturation was confirmed by immunohistochemistry. We conclude that (i) Pgp expression in mouse brain is limited during late embryogenesis and the newborn period; (ii) Pgp expression increases markedly with postnatal maturation, and (iii) by D21 brain Pgp protein expression approximates adult levels.

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Mouse multidrug resistance 1a/3 gene is the earliest known endothelial cell differentiation marker during blood‐brain barrier development

Cited by 73 publications

References 29 publications

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OFMDR1AEXPRESSION

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OFMDR1AEXPRESSION

Activation of β‐catenin signalling by GSK‐3 inhibition increases p‐glycoprotein expression in brain endothelial cells

P-Glycoprotein Expression in Mouse Brain Increases with Maturation

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