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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

Schematic representation of the BBB in health and diseases. Schematic representation of the blood–brain barrier in health (left side) and during pathological breakdown during injury and disease (right side). CNS endothelial cells (pink) form BBB properties, and interact with cells in the blood (RBC-red, leukocyte-blue) and in the neural tissue (pericyte-green, astrocytes-taupe). Many of the BBB properties are altered during diseases such as stroke and MS.
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Figure 2: Schematic representation of the BBB in health and diseases. Schematic representation of the blood–brain barrier in health (left side) and during pathological breakdown during injury and disease (right side). CNS endothelial cells (pink) form BBB properties, and interact with cells in the blood (RBC-red, leukocyte-blue) and in the neural tissue (pericyte-green, astrocytes-taupe). Many of the BBB properties are altered during diseases such as stroke and MS.

Mentions: CNS ECs differ from ECs in non-neural tissues in that they are held together by TJs which greatly restrict the paracellular movement of molecules and ions between the blood and brain. Most of the TJ proteins have been identified by work on epithelial cells, which has demonstrated that TJs are formed by a series of transmembrane proteins, including the claudins [4,5], occludin [6] and junctional adhesion molecules (JAMS) [7] which are linked to the cytoskeleton and adherens junctions by adaptor molecules including ZO-1, ZO-2, Cingulin and others. In particular, claudins are a family of >20 tetraspanin genes in mammals and expression of specific claudin family members in different cellular barriers is thought to be important for the specific paracellular physiology of the barrier [8]. Claudin 5 has been identified as a major constituent of the TJs of CNS ECs (Figure 2). Nitta and colleagues have generated Cldn5 knockout mice [9]. These mice die at birth, and embryos have been shown to have a size selective leakiness of the BBB, with leaks to small molecules (up to 800 Da) but not large molecules (serum albumin, 68 kDa and microperoxidase, 1.9 kDa). The BBB TJs look ultrastructurally normal in the absence of claudin 5 suggesting that other TJ proteins are sufficient to form the structural junctions. In fact, claudin 3 and 12 have been identified as being expressed by CNS ECs [10,11]. The Cldn5 knockout mouse strain is a complete knockout and thus this mouse model cannot be utilized to study the cell autonomous action of claudin 5 in CNS ECs.


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

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

Schematic representation of the BBB in health and diseases. Schematic representation of the blood–brain barrier in health (left side) and during pathological breakdown during injury and disease (right side). CNS endothelial cells (pink) form BBB properties, and interact with cells in the blood (RBC-red, leukocyte-blue) and in the neural tissue (pericyte-green, astrocytes-taupe). Many of the BBB properties are altered during diseases such as stroke and MS.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3675378&req=5

Figure 2: Schematic representation of the BBB in health and diseases. Schematic representation of the blood–brain barrier in health (left side) and during pathological breakdown during injury and disease (right side). CNS endothelial cells (pink) form BBB properties, and interact with cells in the blood (RBC-red, leukocyte-blue) and in the neural tissue (pericyte-green, astrocytes-taupe). Many of the BBB properties are altered during diseases such as stroke and MS.
Mentions: CNS ECs differ from ECs in non-neural tissues in that they are held together by TJs which greatly restrict the paracellular movement of molecules and ions between the blood and brain. Most of the TJ proteins have been identified by work on epithelial cells, which has demonstrated that TJs are formed by a series of transmembrane proteins, including the claudins [4,5], occludin [6] and junctional adhesion molecules (JAMS) [7] which are linked to the cytoskeleton and adherens junctions by adaptor molecules including ZO-1, ZO-2, Cingulin and others. In particular, claudins are a family of >20 tetraspanin genes in mammals and expression of specific claudin family members in different cellular barriers is thought to be important for the specific paracellular physiology of the barrier [8]. Claudin 5 has been identified as a major constituent of the TJs of CNS ECs (Figure 2). Nitta and colleagues have generated Cldn5 knockout mice [9]. These mice die at birth, and embryos have been shown to have a size selective leakiness of the BBB, with leaks to small molecules (up to 800 Da) but not large molecules (serum albumin, 68 kDa and microperoxidase, 1.9 kDa). The BBB TJs look ultrastructurally normal in the absence of claudin 5 suggesting that other TJ proteins are sufficient to form the structural junctions. In fact, claudin 3 and 12 have been identified as being expressed by CNS ECs [10,11]. The Cldn5 knockout mouse strain is a complete knockout and thus this mouse model cannot be utilized to study the cell autonomous action of claudin 5 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