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From the basic biology of cilia to ciliopathy disease states in humans - Peter Swoboda

Evolutionarily RFX transcription factors (TFs) are present only in the unikonts: animals, fungi, choanozoa and amoebozoa. RFX TFs have a unique DNA binding domain with which they bind to the X-box promoter motif (RFX = Regulatory Factor binding to the X-box). Thereby they directly regulate their target genes. In fungi RFX TFs regulate genes involved in cell cycle control, while in animals RFX TFs regulate genes involved in the immune response and in cilia formation and development.

We have carried out searches for X-box promoter motifs in several animal genomes (C. elegans, Drosophila, mouse and humans) and have successfully identified direct RFX TF target genes, many of which we confirmed to be involved in ciliogenesis by using various assays in transgenic C. elegans worms and in transfected mammalian cell lines. Accordingly we were able to assign some of these ciliary genes – upon malfunction – to being at the root of a human disease class termed ciliopathies. We are working on cell biological aspects of human brain-related, suspected ciliopathies. We are also trying to tie together the different biological functions (in ciliogenesis) of direct RFX TF target genes by cross-comparing a large number of candidate X-box regulated genes in a variety of different genomes. With these approaches we will be able to track the RFX TF target gene module from basic biological function to disease states in humans.

sensory cilium

The head of the worm C. elegans is shown. Two bilaterally symmetrical “salt-tasting” sensory neurons are marked with GFP. Through cell-specific genetic rescue experiments the neuron at the top has regained a fully functional sensory cilium (arrowhead) and thus is able to “taste” salt (cf. calcium imaging trace at the left). The neuron at the bottom remains mutant for cilium development and thus is not able to “taste” salt (cf. calcium imaging trace at the left).

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