In COS-7 cells that express FILIP–GFP (green), the levels of endogenous Filamin A (red) is markedly reduced compared with neighbouring cells.

A key event in the development of the human embryonic brain is the migration of neural cells from the ventricular zone through the neocortex. The extracellular factor Reelin provides one cue that tells cells when to stop migrating, but the all-important trigger of when to start migrating has remained a mystery. Sato and colleagues report in Nature Cell Biology that a new molecule, FILIP, has a tight rein on neural cells in the ventricular zone, and prevents their migration by paralysing their motile machinery — the actin cytoskeleton.

The approach that was taken by Sato and colleagues to identify factors that mediate the 'start migrating' signal was to look at which genes are expressed differentially before and after neural migration. Of the genes pulled out, one of them showed an intriguing expression pattern that was restricted to the ventricular zone. This new gene — called FILIP — encodes two proteins, the shorter of which colocalizes with filamentous actin. This led the authors to ask whether FILIP might interact with F-actin. To address this, they conducted a two-hybrid screen and, reassuringly, pulled out the actin-binding factor Filamin A, which is known to be important for mediating cell motility. Consistent with this, both isoforms of FILIP colocalized with Filamin A in vivo.

Can FILIP affect the function of Filamin A? To get a handle on this, Sato and colleagues looked at how FILIP affects cell motility. Cultured cells that expressed filip–gfp showed reduced motility compared with control cells, which led the authors to reason that FILIP might inhibit Filamin A and thereby inhibit cell migration. In support of this, they showed that transfection of COS-7 cells with FILIP-GFP leads to degradation of filamin A (see figure), a process that occurs through a calpain-dependent mechanism.

So, does FILIP regulate migration in vivo in the developing neocortex? Sato and colleagues tested this by introducing FILIP complementary DNAs into the rat neocortex. Consistent with the results from COS-7 cells, they found that the cells that were transfected with filip had altered morphology and impaired migration compared with control cells. Finally, they showed that FILIP and Filamin A interact at the right time and place in vivo, leading to a model in which FILIP degrades Filamin A in the ventricular zone, and prevents premature cell migration. The question now is what the developmental trigger is that mediates FILIP degradation and thereby frees Filamin A from its tethers to allow cell motility. Given the importance of this timing, it seems imperative that this is tightly regulated.