Sufu and Kif7 in limb patterning and development

Background: The vertebrate digit pattern is defined by the morphogen Sonic hedgehog (Shh), which controls the activity of Gli transcription factors. Gli1, 2 and 3 are dynamically expressed during patterning. Downstream of Shh, their activity is regulated by Sufu and Kif7, core components of the Shh signaling cascade. The precise roles of these regulators during limb development have not been fully described. We analyze the role of Sufu and Kif7 in the limb and demonstrate that their loss has distinct and synergistic effects on Gli activity and digit pattern. Results: Using a series of mouse mutants, we show that Sufu and Kif7 are expressed throughout limb development and their deletion has distinct effects on Gli levels and limb formation. Concomitant deletion of Sufu and Kif7 results in constitutive pathway activity and severe limb truncation. This is consistent with the recently published two‐population model, which suggests that precocious activation of Shh signaling inhibits organizing center formation and limb outgrowth. Conclusions: Together, our findings demonstrate that perturbations of Sufu and Kif7 affect Gli activity and recapitulate the full spectrum of vertebrate limb defects, ranging from severe truncation to polydactyly. Developmental Dynamics 244:468–478, 2015. © 2014 Wiley Periodicals, Inc. Key Findings Gli1, Gli2, and Gli3 proteins exhibit dynamic expression across limb patterning. Kif7 and Sufu regulate Gli repressor and activator activity in limb development. Sufu plays distinct roles in early and late limb development. Deletion of Sufu and Kif7 results in distinct types of polydactyly. Sufu and Kif7 play synergistic roles in regulating Gli activator and repressor activity.