By Xylina Gregg, MD, and Josef T. Prchal, MD
2009-03-01
Drs. Gregg and Prchal indicated no relevant conflicts of interest.
Liebner S, Corada M, Bangsow T, et al. Wnt/β-catenin signaling controls development of the blood–brain barrier. J Cell Biol. 2008;183:409-17.
Stenman JM, Rajagopal J, Carroll TJ, et al. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science. 2008;322:1247-50.
That vital organ, the brain, is protected by the blood–brain barrier
(BBB), which is composed of both a physical barrier formed by tight
junctions between brain capillary endothelial cells (ECs) and a
selective active transport system, including a multiple drug resistance
transport system that precludes some drugs and chemicals from entering
the brain. The integrity of the BBB is essential to prevent noxious
substances from entering, while allowing passage of oxygen, glucose,
and other essential nutrients. Disruption of the BBB occurs in brain
ischemia, malignancies, and neurodegenerative disorders including
Alzheimer disease. Some proteins involved in the tight junction
complex, such as claudins (Cldn) and occludins, are essential for BBB
maintenance; claudin 3 (Cldn3), in particular, has brain-specific
expression.1,2 However, the mechanisms by which the BBB is
formed and maintained have not been understood. Recent complementary
reports by Liebner, et al., and Stenman, et al., suggest a crucial role
for Wnt signaling in this process.
The Wnt signaling pathway is involved in many aspects of normal cell
behavior, such as morphogenesis, cell differentiation, and
proliferation.3 Wnt proteins encoded by 19 different genes interact with their receptors, also known as Frizzled proteins, to produce a variety of intracellular events, one of which is stabilization of the protein β-catenin.3
β-catenin, in turn, activates expression of many genes by binding to
several transcription factors. The Wnt pathway is active in brain
development, but it was not previously known that it is also important
for vascular development.
Liebner and colleagues, from Elisabetta Dejana’s lab in Germany,
showed that the Wnt/β-catenin signaling pathway is active in mouse
brain ECs during embryogenesis, but declines after birth and is present
in very small amounts in adult mouse brains. They hypothesized that
this pathway is necessary for the formation and maintenance of the BBB.
Inactivation of β-catenin in ECs was associated with decreased levels
of Cldn3 and increased levels of Cldn5, which is found in non-barrier
types of endothelium, while the reverse was found with activation of
β-catenin. These data suggest that β-catenin controls the formation of
the tight junctions. In vitro treatment of brain ECs by one of the Wnt proteins, Wnt3, activated β-catenin and increased Cldn3 expression and BBB formation.
Stenman and colleagues, from Andrew McMahon’s lab at Harvard, almost
concomitantly reported that the developing neuroepithelium expresses
Wnt7a and Wnt7b proteins and that the surrounding ECs respond to these
signals. The ECs begin expressing glucose transporter (GLUT1), an
essential component of the BBB, and GLUT1 expression ceases in
neuroepithelial cells. Deletion of Wnt7a and Wnt7b
in neuroepithelial progenitor cells or deletion of β-catenin in ECs
results in similar vascular defects of abnormal vascular sprouting and
central nervous system (CNS) hemorrhage in mouse embryos. These data
nicely complement the data described by Liebner, et al.
Wnt signaling appears to be crucial for formation of
the highly specialized neuro-vascular interaction that comprises the
BBB. This work also suggests a role for Wnt signaling and β-catenin
activation in BBB maintenance by affecting the expression of proteins
that make up the tight junctions. Although the details remain to be
elucidated, these findings should open new pathways to explore in order
to explain defects in the BBB caused by disease, as well as to design
new therapies for disorders with impaired BBB. They also open the
possibility of selective manipulation of the system to deliver drugs to
the CNS and, as suggested by Stenman and colleagues, to manipulate
brain tumors, such as glioblastoma multiforme, with enhanced
Wnt/β-catenin signaling and augmented vascular proliferation.
- Morita K, Sasaki H, Furuse M, et al. Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol. 1999;147:185-94.
- Wolburg H, Wolburg-Buchholz K, Kraus J, et al. Localization
of claudin-3 in tight junctions of the blood-brain barrier is
selectively lost during experimental autoimmune encephalomyelitis and
human glioblastoma multiforme. Acta Neuropathol. 2003;105:586-92.
- Grigoryan T, Wend P, Klaus A, et al. Deciphering
the function of canonical Wnt signals in development and disease:
conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev. 2008;22:2308-41.
back to top
