Courtesy of Douglas Epstein, University of Pennsylvania School of Medicine, USA.

The patterning of embryonic neural tissue provides the template for development of the mature nervous system and consequently must proceed with remarkable precision. Sonic Hedgehog (Shh), a protein secreted by the axial mesoderm and the ventral midline of the developing central nervous system, is a key regulator of these patterns of cellular growth and differentiation. Along the dorsoventral axis, a gradient of Shh activity guides the establishment of a variety of cell fates. The role of Shh seems to be more complex along the anteroposterior axis and is thought to depend on interactions between Shh and other signalling pathways, although the genes coordinating Shh expression are poorly understood.

A report from Epstein et. al. in Development demonstrates that within the ventral areas of diencephalon, members of the basic helix–loop–helix–PAS (bHLH–PAS) protein family could activate Shh transcription. By assessing the temporal and spatial overlap between known transcription factors and an Shh reporter construct expressing lacZ in rostal regions, this group revealed that Sim2, a member of the bHLH–PAS family, may function as a Shh activator in developing ventral diencephalon. Moreover, misexpression of Sim2 in transgenic mice led to ectopic expression of Shh. Although Shh expression was maintained in Sim2−/− mutants, it was absent from rostral midbrain and caudal diencephalon of embryos carrying a dominant-negative transgene that disrupts the function of bHLH–PAS proteins. These results indicate that Sim2 and possibly other members of the bHLH–PAS family may be important new regulators of Shh expression.