The development of the brain depends on the precise coordination of growth and patterning mechanisms. Although the patterning mechanisms are becoming well understood, less is known about the factors that influence the overall shape and size of the brain. However, some studies have indicated that the signalling molecule sonic hedgehog (Shh) might be important in controlling growth and cell survival during the later stages of development. Now, as reported in Nature Neuroscience, Britto et al. propose that Shh also controls a much earlier event in brain morphogenesis, namely the expansion, or 'ballooning', of the forebrain and midbrain vesicles.

In the 1950s, Källén showed that the embryonic chick brain collapses if the notochord and anterior hindbrain are separated from the neuroepithelium. At the time, the resulting convoluted appearance of the brain was attributed to overexpansion of the tissue, and this seemed to be borne out by an increase in the number of mitotic figures. Because of this, the phenomenon became known as 'experimental overgrowth'. However, it was later shown that although more cells were in mitosis, their cell cycle was longer, so the net outcome was actually cell loss.

This result indicated that the notochord might secrete a trophic factor that is important for expansion of the brain vesicles. Could this be Shh? To investigate this issue, Britto et al. recreated Källén's collapse phenotype by separating the notochord from the midbrain. They found that this caused a drop in Shh levels, both in the notochord itself and in the floor plate. The expression of patterning genes was largely unaffected, indicating that the main effect was on growth rather than regional patterning.

To confirm that Shh was required for vesicle expansion, Britto et al. then tried grafting Shh-expressing COS cells into the region of the ventral midbrain of the manipulated embryos. They showed that the ballooning of the forebrain and midbrain vesicles was restored in a dose-dependent fashion. They also showed that injection of the Shh inhibitor cyclopamine into intact embryos produced an overall reduction in the size of the head, providing further evidence that Shh controls growth in this region.

This is the first direct demonstration that Shh can regulate the ballooning of the forebrain and midbrain vesicles. This study not only provides a long-overdue explanation for an old phenomenon, but also gives us an intriguing insight into the role of Shh in early brain growth.