Sonic hedgehog (SHH) controls anterior-posterior (A-P) patterning in the mammalian limb. Its expression is normally restricted to the posterior limb bud but when expressed ectopically, it can change digit number and/or identity. Several transcriptional factors regulate Shh expression in the limb bud but how do they function together? On , Xin Sun and co-workers report that interactions between two negative regulators of Shh expression (the ETS transcription factors ETV4/5 and the bHLH transcription factor TWIST1) and a positive regulator of Shh expression (the bHLH transcription factor HAND2) control A-P limb patterning in mice. By examining mutant limb buds, the researchers show that Twist1 is required to inhibit Shh expression in the anterior limb bud, and that it acts with the Etv genes to antagonise Hand2. Moreover, biochemical data indicate that the ETV proteins inhibit Shh expression by regulating the dimerisation of TWIST1/HAND2. Together, these findings highlight the importance of a precise balance between positive and negative regulators of Shh expression during limb A-P patterning.
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