More mitotic cells (pink) are found in developing brains lacking αE-catenin (bottom).


Brain size is kept in check by proteins at cell–cell junctions that act as look-outs for cell density, report Wen-Hui Lien, Olga Klezovitch, Valeri Vasioukhin, and colleagues (Fred Hutchinson Cancer Research Center). The group finds that Hedgehog (Hh)-mediated proliferation is dampened in densely packed cells by an adherens junction component called αE-catenin.

To study the function of adherens junctions, the FHCRC group eliminated αE-catenin, which links the cell junctions to the cytoskeleton. Mutants lacking αE-cadherin in their developing central nervous system had strikingly large brains, with twice as many cells than wild-type controls. Much of this massive—and lethal—excess was due to rapid mitotic cycling of neural progenitor cells.

Microarrays revealed that the expression of fewer than ten genes was altered by the loss of αE-catenin. Several of the up-regulated genes are activators or targets of Hh signaling, which induces hyperproliferation. Blocking this pathway rescued the brain size defect of the αE-catenin mutants. This study provides the first link between Hh signaling and contact-mediated inhibition of proliferation, although just how αE-catenin inhibits Hh is not yet clear.

Junctions in other organs might also pressure cells into down-regulating proliferation via Hh. “In an organism,” says Vasioukhin, “space is a commodity that you have to be aware of. Obviously, cells don't have eyes, so they need another way to ‘see’ how dense the cell population is.” Adherens junctions are the perfect candidate to relay this information, as junctions expand with increasing cell density.

Epithelial tumors often down-regulate cell adhesion proteins, including α-catenin, and may thus bypass the density-dependent Hh control. “When you remove this brake,” says Vasioukhin, “you blind [the cells]. They cannot find out what's happening around them. They wrongly perceive that neighbors are missing and therefore that cell density must be low, so they continue proliferating.”


Lien, W.-H., et al.