Zebrafish models of cystic kidney disease related ciliopathies

Abstract

Cystic kidney diseases are a fascinating cluster of discrete conditions and an important, common cause of established renal failure. Both isolated and syndromic inherited cystic kidney diseases are known to be linked by their pathogenesis involving ciliary dysfunction. Interestingly to date, all mutated genes which have been related to cystic kidney disease, encode proteins which are located on cilia, the basal body or centrosomes and are required for ciliary function. To date, over 50 causal genes have been identified and are capable of causing additional disease phenotypes, such as neurological disorders and blindness, often of variable severity. Understanding this clinical heterogeneity may considerably guide appropriate genetic counselling and screening of patients for relevant complications. Zebrafish are a well-recognised animal model, their advantages of: transparency; conserved genome; representative kidney and rapid external development; make them useful for studying organogenesis in the context of disease. Furthermore the ability to perform combined gene knockdown in zebrafish, to study the effect of oliogenicity, which was proposed to influence clinical phenotypes in cystic kidney disease related ciliopathies, was of interest. Using zebrafish models, this work studied the impact of four key genes, independently and in combination: ahi1, cc2d2a, nphp6 and mks3 on the development of cystic kidney disease and ciliopathy phenotypes, to resemble the human diseases nephronophthisis (NPHP), Joubert syndrome (JBTS) and Meckel Gruber syndrome, (MKS). A frequent finding in zebrafish morphants was a reduction in the number of cilia, which was usually associated with abnormal development of left-right body patterning and cystic kidney disease. Additionally, combined gene knockdown of: nphp6 and cc2d2a; ahi1 and cc2d2a; ahi1 and nphp6 was associated with a synergistic increase in disease phenotypes, suggesting an interaction between these genes. In conclusion, zebrafish are a powerful developmental model to study and ideally improve understanding of cystic kidney disease related ciliopathies.