Primary ciliary dyskinesia (PCD; MIM# 244400) is a rare genetic disorder manifested with recurrent infections of respiratory tract and infertility. The abnormal ciliary motility causes deficient mucociliary transport leading to chronic respiratory infections of the upper and lower airways (i.e., sinusitis and bronchitis). Approximately half of the individuals with PCD displays a situs inversus (thereby defining the Kartagener syndrome), which results from dysfunction of motile embryonic nodal cilia. Moreover, male and female infertility can occur as a result of defective sperm flagella and oviduct cilia, respectively. In humans, mutations in more than 40 genes including the Coiled-Coil Domain Containing 40 (CCDC40) gene are associated with PCD.
Studies in Drosophila have helped to validate several PCD genes whose products are required for cytoplasmic pre-assembly of axonemal dynein motors. Despite that, experimental data about the CG41265 function, the Drosophila ortholoque of CCDC40, are still missing.
Therefore, to investigate the role of CG41265, I will exploit the RNA interference and CRISPR/Cas9 tools to trigger the protein loss of function.
Drosophila melanogaster has always been a leading model organism for the study of many biological phenomena. Despite the evolutionary distance that separates Drosophila from the human specie, the genetic-molecular basis of many biological phenomena are conserved and about 75% of human genes involved in genetic diseases have an orthologous in Drosophila with conserved functions.
Drosophila has recently emerged as a useful model of ciliary motility. Dynein motors and other ciliary components are highly conserved in Drosophila despite the fact that it has only two cell types bearing motile cilia/flagella: the sensory cilium of mechanosensory chordotonal (Ch) neurons and sperm flagellum [1]. In both cell types, the motility machinery is critical for function: if defective, mutant flies are deaf and uncoordinated as the motors are required to generate force during Ch neuron mechanotransduction, and the males are infertile due to immotile sperm [1]. As such, Drosophila is an excellent model for identification and analysis of ciliary motility genes, including dynein assembly factors [2].
[1] - Zur Lage P, Newton FG, Jarman AP. Survey of the Ciliary Motility Machinery of Drosophila Sperm and Ciliated Mechanosensory Neurons Reveals Unexpected Cell-Type Specific Variations: A Model for Motile Ciliopathies. Front Genet. 2019 Feb 1;10:24. doi:10.3389/fgene.2019.00024.
[2] - Zur Lage P, Stefanopoulou P, Styczynska-Soczka K, Quinn N, Mali G, von Kriegsheim A, Mill P, Jarman AP. Ciliary dynein motor preassembly is regulated by Wdr92 in association with HSP90 co-chaperone, R2TP. J Cell Biol. 2018 Jul 2;217(7):2583-2598. doi: 10.1083/jcb.201709026.