Establishing sharp and homogeneous segments in the hindbrain

Studies of the vertebrate hindbrain have revealed parallel mechanisms that establish sharp segments with a distinct and homogeneous regional identity. Recent work has revealed roles of cell identity regulation and its relationships with cell segregation. At early stages, there is overlapping expression at segment borders of the Egr2 and Hoxb1 transcription factors that specify distinct identities, which is resolved by reciprocal repression. Computer simulations show that this dynamic regulation of cell identity synergises with cell segregation to generate sharp borders. Some intermingling between segments occurs at early stages, and ectopic egr2-expressing cells switch identity to match their new neighbours. This switching is mediated by coupling between egr2 expression and the level of retinoic acid signalling, which acts in a community effect to maintain homogeneous segmental identity. These findings reveal an interplay between cell segregation and the dynamic regulation of cell identity in the formation of sharp patterns in the hindbrain and raise the question of whether similar mechanisms occur in other tissues.

Many tissues are patterned by graded signals which regulate the spatial expression of transcription factors that specify regional identity. The initial expression domains of these transcription factors have fuzzy borders, and the proliferation and movements of cells during tissue morphogenesis can potentially cause intermingling between adjacent regions1,2. Nevertheless, a precise pattern subsequently forms in which all cells within each region have the same identity, and there is a straight interface at the border of adjacent domains. This raises the question of how sharp patterns of regional domains are formed and maintained. One general mechanism, which has been extensively studied, is the segregation of cells and restriction of intermingling between adjacent regions, regulated by effectors—such as cadherins or Eph receptors and ephrins—whose expression is coupled to regional identity.

 It will be interesting to explore whether the sharpening of fuzzy borders (Figure 1) involves RA signalling dependent upon how many neighbours have the same or different cyp26 expression level.

These findings raise a number of new questions.