Campagna, Christina et al. (2021) International Worm Meeting "A new role for the conserved G-protein regulator RIC-8/Synembryn in primary cilia biogenesis"

Campagna, Christina, Nechipurenko, Inna

[International Worm Meeting, 2021]

Primary cilia are conserved microtubule-based organelles that protrude from the surface of most metazoan cell types including neurons. They house molecular machinery of all major signaling pathways and play central roles in embryonic development, sensory signal transduction, and adult tissue homeostasis. Due to the central role of cilia in signaling, defects in cilia structure and/or function manifest in multisystemic genetic disorders called ciliopathies. Ciliopathy patients commonly present with neurological deficits that include intellectual disability, anatomical brain abnormalities, and impaired sensory functions. Likewise, cilia and ciliary gene products have been recently associated with neurodevelopmental disorders such as autism spectrum disorder, thereby highlighting the critically important role of cilia in the nervous system. Proteomic and genomic approaches in different models have contributed to the assembly of the ciliary proteome; however, the mechanisms, by which most of the predicted cilia genes modulate cilia function or cellular properties in neurons remain elusive. In a pilot bioinformatics screen for signaling mechanisms of neuronal cilia assembly, we identified the resistance to inhibitors of cholinesterase-8 (ric-8/Synembryn) - a known regulator of G protein alpha biology in species ranging from fungi to vertebrates. We find that ric-8 mutants exhibit marked defects in morphology of complex wing cilia and mild to no defects in assembly of the simple rod-like cilia. Therefore, RIC-8 likely possesses neuron-type-specific functions in ciliogenesis. In line with this hypothesis, GFP-tagged RIC-8 exhibits cell-specific differences in intra-ciliary localization. For example, in PHA/PHB neurons, RIC-8::GFP is detected in the proximal ciliary segment similarly to NPHP-2/inversin. In contrast, RIC-8::GFP appears to be distributed throughout the sensory cilium in the PQR neuron. Here, we will present our ongoing efforts to characterize the role of ric-8 in regulating neuronal cilia morphology in C. elegans.

Christina Dittrich et al. (2006) European Worm Meeting "Identifying Novel Genes Involved in DNA Damage Response Pathways in C. elegans"

Michael O. Hengartner, Christina Dittrich

[European Worm Meeting, 2006]

Christina Dittrich and Michael O. Hengartner1. Upon DNA damage, a cell responds by arresting its cell cycle, changing its transcription patterns, recruiting the repair machinery or, most severely, by executing its own death by apoptosis. Malfunction of any of these pathways allows cells to replicate in spite of DNA lesions, and thus their genomes accumulate mutations and becomes unstable, a hallmark of tumor cells. Therefore, it is not only of paramount biological, but also of high medical interest, to understand the molecular pathways underlying DNA damage responses. Genotoxic stress induces in the germ line of Caenorhabditis elegans a spectrum of DNA damage responses similar to that observed in humans. Because important genes are often conserved throughout evolution, studies in C. elegans might improve our understanding of the molecular programmes safeguarding the genome of human cells. Wild-type C. elegans animals carry out proper DNA damage responses following exposure to ionizing radiation (IR), thus most of their progeny survive. In contrast, radiation-sensitive (Rad) mutants, which are defective in these pathways, show high levels of embryonic lethality upon IR. Taking advantage of this phenotype, we performed a forward genetic screen and identified 17 mutants whose embryos show reduced viability following IR treatment. Two of those mutants, op442 and op444, display a strong Rad phenotype. We are currently mapping the affected genes taking advantage of molecular polymorphisms between the Bristol and the Hawaii isolate of C. elegans. Additionally, we are characterising those two mutants further in order to learn more about the molecular nature underlying the observed defects.