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Hedgehog makes giant brains

More mitotic cells (pink) are found in developing brains lacking E-catenin (bottom). VASIOUKHIN/AAAS

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 E-catenin.

To study the function of adherens junctions, the FHCRC group eliminated E-catenin, which links the cell junctions to the cytoskeleton. Mutants lacking E-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 E-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 E-catenin mutants. This study provides the first link between Hh signaling and contact-mediated inhibition of proliferation, although just how E-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 -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."

Reference:

Lien, W.-H., et al. 2006. Science. 311:1609–1612.[Abstract/Free Full Text]

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 1001K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?