Genetic and protein interaction studies reveal pathway synergy between the ciliary dyslexia candidate genes DYX1C1 and DCDC2

Abstract

Background: DYX1C1 (DNAAF4) and DCDC2 are two of the most replicated dyslexia candidate genes in genetic studies. They both have demonstrated roles in neuronal migration, in cilia growth and function and they both are cytoskeletal interactors. In addition, they both have been characterized as ciliopathy genes. However, their exact molecular functions are still incompletely described. Based on these known roles, we asked whether DYX1C1 and DCDC2 interact on the genetic and the protein level. Results:Here, we report the physical protein-protein interaction of DYX1C1 and DCDC2 via the centrosomal protein CPAP (CENPJ) on exogenous and endogenous levels in different cell models including brain organoids. In addition, we show a synergistic genetic interaction between dyx1c1and dcdc2b in zebrafish exacerbating the ciliary phenotype and suggesting a common pathway in development. Finally, we show a mutual effect on transcriptional regulation among DYX1C1 and DCDC2 in a cellular model. Conclusions: In summary, we describe the physical and functional interaction between the two genes DYX1C1 and DCDC2 that link them to a common pathway. These results contribute to the growing understanding of the molecular roles of DYX1C1 and DCDC2 and set the stage for future functional studies.