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.

In Brief

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.

References

Competing Interests

Drs. Gregg and Prchal indicated no relevant conflicts of interest.