Regulation of wingless signaling by the CKI family in Drosophila limb development

The Wingless (Wg)/Wnt signaling pathway regulates a myriad of developmental processes and its malfunction leads to human disorders including cancer. Recent studies suggest that casein kinase I (CKI) family members play pivotal roles in the Wg/Wnt pathway. However, genetic evidence for the involvement of CKI family members in physiological Wg/Wnt signaling events is lacking. In addition, there are conflicting reports regarding whether a given CKI family member functions as a positive or negative regulator of the pathway. Here we examine the roles of seven CKI family members in Wg signaling during Drosophila limb development. We find that increased CKI epsilon stimulates whereas dominant-negative or a null CKI epsilon mutation inhibits Wg signaling. In contrast, inactivation of CKI alpha by RNA interference (RNAi) leads to ectopic Wg signaling. Interestingly, hypomorphic CKI epsilon mutations synergize with CKI alpha RNAi to induce ectopic Wg signaling, revealing a negative role for CKI epsilon. Conversely, CKIa RNAi enhances the loss-of-Wg phenotypes caused by CKI epsilon null mutation, suggesting a positive role for CKI alpha. While none of the other five CKI isoforms can substitute for CKI alpha in its inhibitory role in the Wg pathway, several CKI isoforms including CG12147 exhibit a positive role based on overexpression. Moreover, loss of Gilgamesh (Gish)/CKI- attenuates Wg signaling activity. Finally, we provide evidence that several CKI isoforms including CKI alpha and Gish/CKI gamma can phosphorylate the Wg coreceptor Arrow (Art), which may account, at least in part, for their positive roles in the Wg pathway. (c) 2006 Elsevier Inc. All rights reserved.