Cells use specialized microtubule based structures called cilia to modulate key sensory and sometimes motile functions. Cilia are essential for development and homeostasis implicating ciliary structural and functional defects in a range of human disorders called ‘Ciliopathies’. In Primary Ciliary Dyskinesia (PCD), ciliary motility is defective; cilia form but fail to generate fluid flow necessary for clearing airways or sperm propulsion leading to male infertility.
The genetic heterogeneity of this disease, with 29 causative loci, compounded by the overlapping clinical and cellular phenotypes of patients with mutations in different PCD genes, complicates our functional understanding of how each gene is involved in building motile cilia.
Cilia motility is dependent on the logistical and physical challenge of assembling huge, multi-molecular motor complexes correctly in the cytoplasm then trafficking them into ciliary compartment. Mutations in PCD genes could affect any stage of this multistep process, both directly and indirectly through feedback mechanisms if this “assembly line” is disrupted.
We have recently generated null mutant mice for one PCD gene, Zmynd10 which recapitulate human PCD disease characteristics as well as cellular defects of cilia motility and dynein motor transport. Using these mutants, we aim to dissect the in vivo role of ZMYND10 on transcriptional and post-translational stability of ciliary motility machinery using NextGen RNASeq and quantitative proteomics. These results will construct a ZMYND10-dependent regulatory network that we will use to examine how adapted it is between different mammalian motile ciliated cell types as well as how conserved it is back to highly modified motile cilia of fruitflies.