Size-selective loosening of the blood-brain barrier in claudin-5–deficient mice

By Takehiro Nitta, Masaki Hata, S. Gotoh, Yoshiteru Seo, H. Sasaki, N. Hashimoto, M. Furuse, S. Tsukita. Journal of Cell Biology, 2003

1,857 citations recorded by the source corpus.

Tight junctions are well-developed between adjacent endothelial cells of blood vessels in the central nervous system, and play a central role in establishing the blood-brain barrier (BBB). Claudin-5 is a major cell adhesion molecule of tight junctions in brain endothelial cells. To examine its possible involvement in the BBB, claudin-5–deficient mice were generated. In the brains of these mice, the development and morphology of blood vessels were not altered, showing no bleeding or edema. However, tracer experiments and magnetic resonance imaging revealed that in these mice, the BBB against small molecules (<800 D), but not larger molecules, was selectively affected. This unexpected finding (i.e., the size-selective loosening of the BBB) not only provides new insight into the basic molecular physiology of BBB but also opens a new way to deliver potential drugs across the BBB into the central nervous system.

Subfields: Neurology, Oncology

View Paper: https://www.semanticscholar.org/paper/4dcd06b3964f18ddadf0487cafffc93029403835

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Neurology

In Oncology

Citations in the corpus

Crosstalk of tight junction components with signaling pathways. (2008, background): “Thus endothelial cells of the brain express claudins-3, -5 and -12 [26–28], kidney endothelia have claudins-5 and -15 [24,27], while placental endothelia exhibit claudins-1, -3 and -5 [29,30].”
Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. (2008, background): “…immune response and inflammation (Greer, 2002); Amn (Amnionless), a transmembrane protein essential for amnion formation during embryonic development (Kalantry et al., 2001); and Cldn5 (Claudin 5), a component of tight junctions involved in formation of the blood-brain barrier (Nitta et al., 2003).”
The blood-brain barrier. (2015, background): “Claudin-5 has been shown to be highly expressed by CNS ECs, and mice that lack claudin-5 have a sizeselective leak of the BBB (Morita et al. 1999; Nitta et al. 2003).”
Blood‐brain barrier‐specific properties of a human adult brain endothelial cell line (2005, background): “terms of the relative contribution of these proteins to tight junction formation, it is of interest to note that, although occludin unexpectedly appeared to be dispensable (43), loosening of the BBB was reported in claudin-5-deficient mice (44), highlighting the key contribution of this adhesion mol”
Structure and function of claudins. (2008, background): “Inner ear [57] – Extension in ECL2 [7] – Stomach, lung [61] 19 – Kidney, retina [102], – Reduces paracellular cation permeability in MDCK-II, increases TER [48] – Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, visual impairments; hypomagnesaemia mutations in TMD1, 2 and ECL1 (Q57”
Permeability Studies on In Vitro Blood–Brain Barrier Models: Physiology, Pathology, and Pharmacology (2005, background): “Another good example is that complete loss of claudin-5 in knockout mice results in a selective increase in paracellular permeability for small molecules (Nitta et al., 2003).”
The tight junction: a multifunctional complex. (2004, methodology): “Similarly, mice deficient in claudin-1 (49), claudin-5 (109), or claudin-11 (57) revealed novel roles in the TJs of specific tissues, whereas overexpression of claudin-6 resulted in aberrant expression of both epidermal differentiation markers and of other claudins.”
The molecular basis of water transport in the brain (2003, background): “Water passage between the endothelial cells is restricted by tight junctions, which form an essential part of the blood–brain barrie”
The blood-brain barrier in health and chronic neurodegenerative disorders. (2008, neutral): “Claudin-5, -3, and -12 are localized at the BBB (Nitta et al., 2003; Wolburg, 2006), whereas the presence of claudin-1 is controversial (Lee et al., 2003).”
Physiology and function of the tight junction. (2009, background): “…claudins have now been deleted from mice and the resulting phenotypes are consistent with a barrier role for claudins 1 (Ladwein et al. 2005), 5 (Nitta et al. 2003), 11 (Gow et al. 2000), 14 (Ben Yosef et al. 2003), and 15 (Tamura et al. 2008), although the phenotypes are not easily explained…”
Blood–brain Barrier: Structural Components and Function Under Physiologic and Pathologic Conditions (2006, neutral): “BMVEC express predominantly claudin-3 and claudin-5 (Nitta et al. 2003; Hawkins and Davis 2005).”