Polycystin-1 (PC1), encoded by the PKD1 gene, is a large transmembrane glycoprotein that orchestrates critical cellular processes—including cell–cell and cell–matrix interactions, calcium signaling, and mechanosensation—in renal tubular epithelial cells. PC1 regulates various aspects of cellular function, including signal transduction, cytoskeletal remodeling, and cell adhesion. It forms a functional complex with Polycystin-2 (PC2), the product of the PKD2 gene, to maintain intracellular calcium homeostasis and facilitate mechanotransduction ^[1]. Disruption of PC1 signaling, due to PKD1 mutations—which account for approximately 85% of autosomal dominant polycystic kidney disease (ADPKD) cases—undermines these regulatory pathways, promoting abnormal cell proliferation and cyst formation ^[2]. Clinically, ADPKD is characterized by the progressive development of multiple fluid-filled cysts, renal enlargement, hypertension, and eventual progression to end-stage kidney disease (ESKD). With a global incidence estimated at 1 in 400 to 1 in 1000 individuals, ADPKD affects nearly 500,000 people in the United States alone and frequently involves extra-renal manifestations, including the heart, liver, pancreas, spleen, and arachnoid membrane ^[3]. Notably, genotypic heterogeneity exists, with PKD1 mutations often associated with an earlier onset and more aggressive disease course ^[2-3]. Traditional systemic Pkd1 knockout models are typically embryonically lethal, precluding long-term pathogenesis studies. In contrast, inducible, kidney-specific conditional knockout models using the Cre-LoxP system recapitulate the clinical features of human ADPKD and permit the investigation of disease progression in adult mice ^[4-5]. Chronic-PKD mice are an inducible conditional Pkd1 knockout model generated by crossing Pkd1-flox mice with kidney-specific, tamoxifen-inducible Cre mice (Cdh16-MerCreMer mice). Preliminary data show that palpable renal enlargement occurs at 6 weeks after tamoxifen induction. At 10 weeks post-induction, a polycystic kidney phenotype is visible upon dissection, with no mortality observed and a more pronounced phenotype in male mice. We will continue monitoring this model to characterize late-stage phenotypes and the overall disease progression.

Polycystin-1 (PC1), encoded by the PKD1 gene, is a large transmembrane glycoprotein that orchestrates critical cellular processes—including cell–cell and cell–matrix interactions, calcium signaling, and mechanosensation—in renal tubular epithelial cells. PC1 regulates various aspects of cellular function, including signal transduction, cytoskeletal remodeling, and cell adhesion. It forms a functional complex with Polycystin-2 (PC2), the product of the PKD2 gene, to maintain intracellular calcium homeostasis and facilitate mechanotransduction ^[1]. Disruption of PC1 signaling, due to PKD1 mutations—which account for approximately 85% of autosomal dominant polycystic kidney disease (ADPKD) cases—undermines these regulatory pathways, promoting abnormal cell proliferation and cyst formation ^[2]. Clinically, ADPKD is characterized by the progressive development of multiple fluid-filled cysts, renal enlargement, hypertension, and eventual progression to end-stage kidney disease (ESKD). With a global incidence estimated at 1 in 400 to 1 in 1000 individuals, ADPKD affects nearly 500,000 people in the United States alone and frequently involves extra-renal manifestations, including the heart, liver, pancreas, spleen, and arachnoid membrane ^[3]. Notably, genotypic heterogeneity exists, with PKD1 mutations often associated with an earlier onset and more aggressive disease course ^[2-3]. Traditional systemic Pkd1 knockout models are typically embryonically lethal, precluding long-term pathogenesis studies. In contrast, inducible, kidney-specific conditional knockout models using the Cre-LoxP system recapitulate the clinical features of human ADPKD and permit the investigation of disease progression in adult mice ^[4-5]. Acute PKD (inducible) mice represent an inducible conditional Pkd1 knockout model generated by crossing Pkd1-floxed mice with kidney-specific, tamoxifen-inducible Cre mice (Cdh16-MerCreMer). Offspring were induced with tamoxifen during lactation to achieve targeted deletion of Pkd1 within renal tubular epithelial cells. Preliminary observations at three weeks post-induction reveal pronounced polycystic kidney disease phenotypes, including the emergence of renal cysts, a marked increase in kidney volume, and elevated serum blood urea nitrogen (BUN) levels. We will continue to monitor this model to assess its late-stage phenotypes and overall disease progression.

Pkd1 is located on chromosome 17 of mice. Nuclease Technology was used to design sgRNA; Pkd1 knockout mice were obtained by applying high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.

Pkd1 is located on chromosome 17 of mice. SgRNA and ssDNA were designed using Nuclease Technology; Pkd1 conditional knockout mice were obtained by high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.

Nlgn3 is located on chromosome X of mice. Nuclease Technology will be used to design sgRNA; Nlgn3 knockout mice will be obtained by applying high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.

Exosc2 is located on chromosome 2 of mice. SgRNA and ssDNA will be designed using Nuclease Technology; Exosc2 conditional knockout mice will be obtained by high-throughput electroporation of fertilized eggs. After sexual maturity, sperm will be collected for cryopreservation.