The guidance molecule netrin-1 is famous for its role in telling axons — the long extensions sent out by nerve cells — where they should and shouldn't go in the nervous system. Reporting in Developmental Cell (4, 371–382; 2003), Karpagam Srinivasan et al. extend the repertoire of netrin-1 activities to non-neuronal tissues, showing that it also acts to keep cells stuck together during the development of mammary glands.

It was already known that netrins are secreted by many cells outside the nervous system, but until now no one had really worked out what they were doing. Srinivasan et al. looked more closely at where netrin-1 occurs in the developing mammary glands of mice, and found that it surrounds the cap cells — the single layer of cells that caps the developing gland, or bud — in a pattern that is complementary to one of its receptors, neogenin.

Extrapolating from netrin-1's function in the nervous system, it might be predicted that it provides a positional cue to guide moving cells within the mammary gland. Surprisingly, the authors found that, instead, netrin-1 prevents cap-cell movement. Loss of either netrin-1 or neogenin disrupted adhesion between the cap-cell layer and adjacent cells, and resulted in cap cells moving into regions where they would not normally go, as seen in these images of normal (top) and netrin-deficient (bottom) buds. Furthermore, addition of netrin-1 to isolated neogenin-producing cells caused them to aggregate. So it seems that netrin-1 may be required in the developing mammary gland simply to make sure that cells stick together.

The authors are now investigating the long-term consequences of loss of netrin-1 for mammary-gland development, and in particular the possibility that these tissue disruptions increase susceptibility to cancer. At a more basic level, how does the binding of netrin-1 to neogenin immobilize cells? Studies of netrin-1 in the nervous system provide some hints, but there may be more surprises in store.