Maurya, Ashish Kumar et al. (2022) MicroPubl Biol

Maurya, Ashish Kumar, Sengupta, Piali

[MicroPubl Biol, 2022]

The conserved CCRK, RCK, and CDKL5 kinases regulate cilia length in diverse organisms. In C. elegans , DYF-18 CCRK regulates DYF-5 RCK to shape both simple and complex cilia morphologies. The CDKL5 ortholog CDKL-1 has also been suggested to act downstream of DYF-18 but independently of DYF-5 to regulate lengths of simple rod-like cilia. Here we show that CDKL-1 is largely dispensable for regulation of complex cilia structures. Using genetic epistasis experiments, we confirm that CDKL-1 and DYF-5 act independently to control cilia architecture. Our results indicate that multiple kinases act via distinct pathways to regulate unique cilia ultrastructures.

Maurya, Ashish et al. (2021) International Worm Meeting "xbx-4, a novel Joubert syndrome-related gene, acts in the CCRK/RCK kinase cascade to regulate cilia length and morphology"

Sengupta, Piali, Maurya, Ashish

[International Worm Meeting, 2021]

Primary cilia are microtubule-based sensory organelles that are critical for sensing and transducing extracellular cues in multiple cellular contexts. The core ultrastructure of cilia is highly conserved and formed by stereotyped mechanisms. To fulfill their wide array of context-specific sensory functions, cilia exhibit diverse shapes and sizes. How cilia with specialized morphologies are generated remains unclear. In C. elegans, a subset of head amphid sensory neurons including the AWA olfactory neurons contains elaborate and complex cilia. I found that a highly conserved kinase cascade comprising the DYF-18 CCRK and DYF-5 RCK-related kinases plays a major role in regulating AWA cilia length and branching. Genetic and imaging experiments suggest that these kinases destabilize axonemal microtubules to promote AWA cilia branching. Regulators of this kinase cascade are largely unknown. Using a forward genetic screen for mutants that suppress the effects of overexpressed RCK kinase, I identified XBX-4, a novel regulator of the CCRK/RCK kinase cascade. I show that XBX-4 primarily regulates CCRK activity, thereby controlling RCK function and localization. XBX-4 contains a Domain of Unknown Function, DUF3719, that it shares with just two proteins (FAM149A and FAM149B1) in the human proteome. Rare mutations in the DUF3719 domain of FAM149B1 result in the ciliopathy Joubert syndrome via unknown mechanisms. My results suggest that xbx-4 encodes the functional ortholog of FAM149b1 and exerts its effects on cilia structure and function by controlling the activity of the CCRK/RCK kinase cascade.