Mechanisms of Cyst Initiation in Autosomal Dominant Polycystic Kidney Disease
Year: 2026
Type: dissertation
Abstract: Autosomal dominant polycystic kidney disease is a common inherited disorder caused by loss of function in the polycystin proteins. Affected individuals develop fluid-filled renal cysts that progressively compromise kidney function and can ultimately require renal replacement therapy. Despite decades of research, the earliest events that initiate cyst formation remain poorly understood. This thesis uses Xenopus tadpoles to combine in vivo disease modeling with the development of precise genome engineering methods. By disrupting polycystin function with CRISPR-Cas9 and performing live imaging of renal tubules, we show that cysts initiate when tubules fail to reconstrict after a transient, physiological dilation. This dilation can be triggered by luminal obstruction and depends on cilia, whereas reconstriction requires polycystin-dependent activation of actomyosin contractility. When this response is lost, sustained epithelial stretch promotes cyst formation. We further identify molecular regulators of dilation through a phosphoproteomic screen and test candidate factors by targeted functional perturbation. In parallel, we develop a method for precise and predictable genomic integration by leveraging the reproducibility of repair outcomes at genome-donor junctions. We demonstrate efficient in-frame integration for endogenous protein tagging, perform targeted nucleotide changes, and provide an accompanying protocols resource to support broad adoption of the workflow. $\textit{Full-text embargoed until: 2027-05-08}$
DOI: 10.5167/uzh-434717
Author: Yamamoto, Taiyo Daniel
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7166093837