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Genetic mouse models to study blood-brain barrier development and function.

Sohet F, Daneman R - Fluids Barriers CNS (2013)

Bottom Line: The blood-brain barrier (BBB) is a complex physiological structure formed by the blood vessels of the central nervous system (CNS) that tightly regulates the movement of substances between the blood and the neural tissue.Recently, the generation and analysis of different genetic mouse models has allowed for greater understanding of BBB development, how the barrier is regulated during health and its response to disease.Here we discuss: 1) Genetic mouse models that have been used to study the BBB, 2) Available mouse genetic tools that can aid in the study of the BBB, and 3) Potential tools that if generated could greatly aid in our understanding of the BBB.

View Article: PubMed Central - HTML - PubMed

Affiliation: UCSF Department of Anatomy, 513 Parnassus Ave HSW1301, San Francisco, 94117, California, USA. Fabien.sohet@ucsf.edu.

ABSTRACT
The blood-brain barrier (BBB) is a complex physiological structure formed by the blood vessels of the central nervous system (CNS) that tightly regulates the movement of substances between the blood and the neural tissue. Recently, the generation and analysis of different genetic mouse models has allowed for greater understanding of BBB development, how the barrier is regulated during health and its response to disease. Here we discuss: 1) Genetic mouse models that have been used to study the BBB, 2) Available mouse genetic tools that can aid in the study of the BBB, and 3) Potential tools that if generated could greatly aid in our understanding of the BBB.

No MeSH data available.


Related in: MedlinePlus

Abcb1a/Abcb1b/Bcrp triple knockout mice have a leaky BBB to Rhodamine123. Adult wild type (C) or Abcb1a/Abcb1b/Bcrp triple knockout mice (3KO) were given an intravenous injection of Rhodamine123 (10 ng). After 1 hour the blood compartment was removed by transcardiac perfusion with PBS, the brains were removed, hemisected down the midline and imaged for Rhodamine123 fluorescence with a Fujifilm imager LAS 4000. Figure 3 represents an image of the hemisected brains with the cerebellum at the top of the image and frontal cortex towards the bottom of the image. More Rhodamine123 (dark color) was observed in Abcb1a/Abcb1b/Bcrp triple knockout mice compared with littermate controls. To demonstrate the consistency of the phenotype between different animals, 3 wild-type and 3 Abcb1a/Abcb1b/Bcrp triple knockout mice brains were utilized.
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Figure 3: Abcb1a/Abcb1b/Bcrp triple knockout mice have a leaky BBB to Rhodamine123. Adult wild type (C) or Abcb1a/Abcb1b/Bcrp triple knockout mice (3KO) were given an intravenous injection of Rhodamine123 (10 ng). After 1 hour the blood compartment was removed by transcardiac perfusion with PBS, the brains were removed, hemisected down the midline and imaged for Rhodamine123 fluorescence with a Fujifilm imager LAS 4000. Figure 3 represents an image of the hemisected brains with the cerebellum at the top of the image and frontal cortex towards the bottom of the image. More Rhodamine123 (dark color) was observed in Abcb1a/Abcb1b/Bcrp triple knockout mice compared with littermate controls. To demonstrate the consistency of the phenotype between different animals, 3 wild-type and 3 Abcb1a/Abcb1b/Bcrp triple knockout mice brains were utilized.

Mentions: CNS ECs express efflux transporters to eliminate potential toxins from the CNS. These include members of the ATP-binding cassette (ABC) transporters, which utilize the hydrolysis of ATP to transport a wide variety of substrate molecules against their concentration gradient. In particular, CNS ECs express P-glycoprotein (Pgp/Mdr1/Abcb1) and the breast cancer resistance protein (Bcrp/Abcg2) (Figure 2), each of which has diverse but potentially overlapping substrate specificity [29-31]. The mouse genome contains two Pgp genes: Abcb1a and Abcb1b. Several mouse lines are available for studying Abcb1a, including targeted gene disruption (Abcb1atm1bor), a Cre/lox regulated luciferase targeted into the Abcb1a locus (Abcb1atm1Kane) and a spontaneous mutation (Abcb1amds) that has a long terminal repeat of the ecotropic murine leukemia virus inserted into an intron [32-34]. Mice homozygous for Abcb1atm1bor allele have a BBB that is more permeable to specific molecules including different xenobiotics and drugs [32]. Because Pgp has 2 isoforms, Doran and colleagues generated a double knockout mouse of Abcb1a and Abcb1b to study drug delivery [35]. Finally, as Pgp and Bcrp can transport some of the same substrates, the Abcb1a/Abcb1b/Bcrp triple knockout mouse was genetically engineered [36] and found to have a leaky BBB for many lipophilic xenobiotics, including rhodamine123, compared to their wild type (WT) littermates (Figure 3). These mice are very useful to study brain neuroprotection and neurotoxicity [37]. However one has to keep in mind that in these widely-used knockout strains, the efflux transporters are deleted in every cell throughout the body, and not specifically in CNS ECs.


Genetic mouse models to study blood-brain barrier development and function.

Sohet F, Daneman R - Fluids Barriers CNS (2013)

Abcb1a/Abcb1b/Bcrp triple knockout mice have a leaky BBB to Rhodamine123. Adult wild type (C) or Abcb1a/Abcb1b/Bcrp triple knockout mice (3KO) were given an intravenous injection of Rhodamine123 (10 ng). After 1 hour the blood compartment was removed by transcardiac perfusion with PBS, the brains were removed, hemisected down the midline and imaged for Rhodamine123 fluorescence with a Fujifilm imager LAS 4000. Figure 3 represents an image of the hemisected brains with the cerebellum at the top of the image and frontal cortex towards the bottom of the image. More Rhodamine123 (dark color) was observed in Abcb1a/Abcb1b/Bcrp triple knockout mice compared with littermate controls. To demonstrate the consistency of the phenotype between different animals, 3 wild-type and 3 Abcb1a/Abcb1b/Bcrp triple knockout mice brains were utilized.
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Figure 3: Abcb1a/Abcb1b/Bcrp triple knockout mice have a leaky BBB to Rhodamine123. Adult wild type (C) or Abcb1a/Abcb1b/Bcrp triple knockout mice (3KO) were given an intravenous injection of Rhodamine123 (10 ng). After 1 hour the blood compartment was removed by transcardiac perfusion with PBS, the brains were removed, hemisected down the midline and imaged for Rhodamine123 fluorescence with a Fujifilm imager LAS 4000. Figure 3 represents an image of the hemisected brains with the cerebellum at the top of the image and frontal cortex towards the bottom of the image. More Rhodamine123 (dark color) was observed in Abcb1a/Abcb1b/Bcrp triple knockout mice compared with littermate controls. To demonstrate the consistency of the phenotype between different animals, 3 wild-type and 3 Abcb1a/Abcb1b/Bcrp triple knockout mice brains were utilized.
Mentions: CNS ECs express efflux transporters to eliminate potential toxins from the CNS. These include members of the ATP-binding cassette (ABC) transporters, which utilize the hydrolysis of ATP to transport a wide variety of substrate molecules against their concentration gradient. In particular, CNS ECs express P-glycoprotein (Pgp/Mdr1/Abcb1) and the breast cancer resistance protein (Bcrp/Abcg2) (Figure 2), each of which has diverse but potentially overlapping substrate specificity [29-31]. The mouse genome contains two Pgp genes: Abcb1a and Abcb1b. Several mouse lines are available for studying Abcb1a, including targeted gene disruption (Abcb1atm1bor), a Cre/lox regulated luciferase targeted into the Abcb1a locus (Abcb1atm1Kane) and a spontaneous mutation (Abcb1amds) that has a long terminal repeat of the ecotropic murine leukemia virus inserted into an intron [32-34]. Mice homozygous for Abcb1atm1bor allele have a BBB that is more permeable to specific molecules including different xenobiotics and drugs [32]. Because Pgp has 2 isoforms, Doran and colleagues generated a double knockout mouse of Abcb1a and Abcb1b to study drug delivery [35]. Finally, as Pgp and Bcrp can transport some of the same substrates, the Abcb1a/Abcb1b/Bcrp triple knockout mouse was genetically engineered [36] and found to have a leaky BBB for many lipophilic xenobiotics, including rhodamine123, compared to their wild type (WT) littermates (Figure 3). These mice are very useful to study brain neuroprotection and neurotoxicity [37]. However one has to keep in mind that in these widely-used knockout strains, the efflux transporters are deleted in every cell throughout the body, and not specifically in CNS ECs.

Bottom Line: The blood-brain barrier (BBB) is a complex physiological structure formed by the blood vessels of the central nervous system (CNS) that tightly regulates the movement of substances between the blood and the neural tissue.Recently, the generation and analysis of different genetic mouse models has allowed for greater understanding of BBB development, how the barrier is regulated during health and its response to disease.Here we discuss: 1) Genetic mouse models that have been used to study the BBB, 2) Available mouse genetic tools that can aid in the study of the BBB, and 3) Potential tools that if generated could greatly aid in our understanding of the BBB.

View Article: PubMed Central - HTML - PubMed

Affiliation: UCSF Department of Anatomy, 513 Parnassus Ave HSW1301, San Francisco, 94117, California, USA. Fabien.sohet@ucsf.edu.

ABSTRACT
The blood-brain barrier (BBB) is a complex physiological structure formed by the blood vessels of the central nervous system (CNS) that tightly regulates the movement of substances between the blood and the neural tissue. Recently, the generation and analysis of different genetic mouse models has allowed for greater understanding of BBB development, how the barrier is regulated during health and its response to disease. Here we discuss: 1) Genetic mouse models that have been used to study the BBB, 2) Available mouse genetic tools that can aid in the study of the BBB, and 3) Potential tools that if generated could greatly aid in our understanding of the BBB.

No MeSH data available.


Related in: MedlinePlus