Functional Characterisation of the Conserved FOXJ1 Effector CFAP206 in Mouse and Xenopus

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Impaired cilia functions account for a growing list of human diseases, collectively referred to as ciliopathies. Primary ciliary dyskinesia (PCD) is a distinct group of ciliopathies specifically caused by non-functional motile cilia due to mutations in genes required for the assembly and function of these organelles. Only a subset of genes mutated in PCD patients is known. In vertebrates the transcription factor Foxj1 is a key regulator of the formation of motile cilia in numerous cell types. Thus, genes regulated by FOXJ1 are likely to be important for the formation and/or function of motile cilia and good candidates for genes affected in PCD.We have isolated novel Foxj1 target genes which are selectively active in ciliated cells and tissues during mouse and frog embryogenesis. One such gene, Cfap206, encodes a protein of unknown function that localizes to the basal body, specifically to a poorly characterized ciliary appendage called the rootlet. A targeted mutation of Cfap206 in mice causes PCD-related phenotypes in some tissues with motile cilia, i.e. impaired sperm function and hydrocephalus. The latter phenotype was also observed in morphant Xenopus tadpoles, along with phenotypes of the embryonic kidney, the pronephros, and the mucociliary epithelium of the larval epidermis, indicating malfunctioning motile cilia in these tissues. Based on our extensive preliminary data, we hypothesize that Cfap206 plays a pivotal role at the ciliary basal body/rootlet to regulate motility and coordinated extracellular fluid flow downstream of Foxj1.To determine the function of Cfap206 we plan to comprehensively analyse the physiological and cellular functions of Cfap206 in vivo in PCD target tissues (sperm, ependyma, mucociliary epithelia). To study the biochemical properties and functions of Cfap206 we plan to identify interaction partners and analyse their significance for Cfap206 function. To achieve these goals, we will combine advanced developmental, molecular, cellular and biochemical approaches in mouse and frog embryos in vivo and in vitro. The results of this complementary approach in two species, both of which represent valid model organisms for the study of PCD/ciliopathies, can be expected to provide important new insights into the tissue-specific requirements for motile cilia, particularly rootlet function and sperm motility.