"Human autosomal dominant polycystic kidney disease (ADPKD) is the most frequently inherited monogenic disorder and presents with renal cysts and a host of extrarenal manifestations. A majority of cases of ADPKD are caused by mutations in PKD1, a gene that encodes the protein polycystin-1 (PC1). We investigate several Pkd1 transgenic mouse lines in order to study the role PC1 plays in renal and extrarenal homeostasis and cystogenesis: (1) a full- length, systemic overexpression transgenic Pkd1 model, Pkd1TAG, (2) a full-length, renal- targeted transgenic Pkd1 model, SBPkd1TAG, (3) a Pkd1 cDNA renal-targeted transgenic model, SBP65, and (4) a pancreas-specific Cre-mediated deletion of Pkd1, Pdx1-Cre;Pkd1flox/flox. Our results show that the Pkd1TAG transgene can replace endogenous Pkd1 on a Pkd1-/- background, and that overexpression of our transgene, up to 10-fold, does not cause early renal cystogenesis or other extrarenal manifestations of ADPKD. By replacing endogenous regulatory elements with the renal-specific “SB” to target expression of our transgene preferentially to the kidneys, we were able to highlight the importance of the native Pkd1 regulatory elements for proper renal homeostasis, as inadequate spatio-temporal expression of PC1 in the SBPkd1TAG on a Pkd1-/- background, even when levels of gene and protein are similar or increased relative to wildtype, leads to development of renal cysts in young pups. Further, by removing Pkd1 intron sequences in the Pkd1 gene, the SBP65 transgenic line displayed an exacerbated PKD phenotype and reveal the presence of additional regulatory elements within the intronic region that likely confer proper and/or efficient spatio-temporal regulation. Because our results also show that increased Pkd1 levels from the SBPkd1TAG transgene intercrosses correlate with a later ADPKD phenotype onset and prolonged survival, we propose that dosage-reduction of PC1-producing functional Pkd1 gene may cause early onset, rapid cystogenesis; chimeric cellular expression may also be culpable. In addition to renal studies, we also investigated dosage-reduction in the pancreas. Results from the Pkd1TAG mouse line suggest that overexpression is not a pathogenetic mechanism of pancreatic cystogenesis, as no cystic pancreatic phenotype was observed in those mice. Analysis of the pancreas from SBPkd1TAG mice on a Pkd1-/- background suggests that either dosage-reduction or cellular chimerism of PC1 can induce cyst formation. Further, ablation of Pkd1 in the pancreas alone, using Pdx1-Cre mice with two floxed Pkd1 alleles, was sufficient to induce severe pancreatic cysts, similar to what is seen in Pkd1-/-. Both Pdx1- Cre;Pkd1flox/flox and Pkd1-/- die at or before birth, possibly implicating pancreatic cysts to perinatal lethality. This study demonstrates the effectiveness of our transgenic Pkd1 in replacing endogenous Pkd1 in the kidneys and pancreas. Additionally, we conclude that proper Pkd1/PC1 spatio-temporal regulation by native regulatory elements is necessary for renal homeostasis. Additionally, this dysregulation alone is sufficient to induce renal cystogenesis. In the pancreas, we implicate gene-dosage reduction and total ablation, as well as cellular chimerism, but not overexpression, as mechanisms in pancreatic cyst formation. Through delineation of underlying pathogenetic mechanisms of cyst formation in ADPKD mouse models, we have identified crucial Pkd1 regulatory regions and molecular signaling systems that can serve to device potential therapeutic design for treatment and prevention of ADPKD"--