Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis.
Hedgehog (Hh) signalling is essential for several aspects of embryogenesis. In Drosophila, Hh transduction is mediated by a cytoplasmic signalling complex 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 mammals. 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 orthologue, 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.
Wilson
Christopher W
CW
Cardiovascular Research Institute, University of California, San Francisco, California 94158, USA.
Nguyen
Catherine T
CT
Chen
Miao-Hsueh
MH
Yang
Jehn-Hsiahn
JH
Gacayan
Rhodora
R
Huang
Jie
J
Chen
Jau-Nian
JN
Chuang
Pao-Tien
PT
D000818:Animals; D060466:Axin Protein; D002923:Cilia / Q000502:physiology*; D053823:Hedgehog Proteins / Q000502:physiology*; D016547:Kinesins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology
D060466:Axin Protein; D053823:Hedgehog Proteins; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D016547:Kinesins