Modeling Complex Developmental Disease: The Case of Polycystic Kidney Disease

Abstract

Both genetics and the environment affect the phenotypes of polycystic kidney diseases (PKD), such as autosomal dominant (AD) PKD, autosomal recessive (AR) PKD and nephronophthisis (NPH). Variable phenotypes, pleiotropy, divergent severity and progression, even in family members who inherited the same disease-causing mutation(s), signal the involvement of networked genes and modifiers. Several PKD-linked genes function in development and renal tubule morphogenesis. Cystic renal tissues feature metabolic remodeling, functional reprogramming and dysregulation of several shared factors and pathways. ADPKD, ARPKD and NPH partially phenocopy each other. Understanding the developmental arc of cystic kidney disease and its complex phenotypes would improve diagnostics and help develop effective personalized treatments. However, this is challenging to study in vertebrate systems due to genetic redundancy, functional overlap, and a dearth of genetic tools. Underused in this context, Drosophila melanogaster offers high genomic and pathway conservation, a wealth of genetic tools, and rapid generation times, making it a reliable and sustainable model for mechanistic, genome-wide, and precision medicine studies. Here, we surveyed ADPKD, ARPKD, and NPH, compared renal and extrarenal phenotypes, and examined the network of shared and unique contributors, their healthy and diseased functions and conservation from the perspective of mechanistic whole-animal modeling.