Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis

Abstract

Hedgehog (Hh) signalling is important in development and disease. In this study Pao-Tien Chuang and colleagues study the function and evolution of Fused (Fu), which is required for Hh signalling in Drosophila but not in mice. They find that the function of Fu has changed over evolution. In mice, Fu is required for the formation of motile cilia. In contrast, in zebrafish, Fu is required for both Hh signalling and cilia formation thus representing an evolutionary intermediate. This study reveals a novel pathway for cilia assembly and provides insight into the evolution of the Hh signalling cascade. Hedgehog signalling is important in development and disease; Fused is required for Hedgehog signalling in Drosophila but not in mice. Here it is shown how the function of Fused has evolved by studying its role in zebrafish relative to mice, providing insight into the evolution of the Hedgehog signalling cascade. Hedgehog (Hh) signalling is essential for several aspects of embryogenesis1,2. In Drosophila, Hh transduction is mediated by a cytoplasmic signalling complex3,4,5 that includes the putative serine-threonine kinase Fused (Fu) and the kinesin Costal 2 (Cos2, also known as Cos), yet Fu does not have a conserved role in Hh signalling in mammals6,7. Mouse Fu (also known as Stk36) mutants are viable and seem to respond normally to Hh signalling. Here we show that mouse Fu is essential for construction of the central pair apparatus of motile, 9+2 cilia and offers a new model of human primary ciliary dyskinesia. We found that mouse Fu physically interacts with Kif27, a mammalian Cos2 orthologue8, and linked Fu to known structural components of the central pair apparatus, providing evidence for the first regulatory component involved in central pair construction. We also demonstrated that zebrafish Fu is required both for Hh signalling and cilia biogenesis in Kupffer’s vesicle. Mouse Fu rescued both Hh-dependent and -independent defects in zebrafish. Our results delineate a new pathway for central pair apparatus assembly, identify common regulators of Hh signalling and motile ciliogenesis, and provide insights into the evolution of the Hh cascade.