{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T07:56:49Z","timestamp":1793692609130,"version":"4.5.1"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","funder":[{"DOI":"10.13039\/100001296","name":"PKD Foundation","doi-asserted-by":"publisher","award":["196G14a"],"award-info":[{"award-number":["196G14a"]}],"id":[{"id":"10.13039\/100001296","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001296","name":"PKD Foundation","doi-asserted-by":"publisher","award":["199G14"],"award-info":[{"award-number":["199G14"]}],"id":[{"id":"10.13039\/100001296","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001296","name":"PKD Foundation","doi-asserted-by":"publisher","award":["232G18"],"award-info":[{"award-number":["232G18"]}],"id":[{"id":"10.13039\/100001296","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001463","name":"American Society of Nephrology","doi-asserted-by":"publisher","award":["Norman Siegel Research Scholar Grant"],"award-info":[{"award-number":["Norman Siegel Research Scholar Grant"]}],"id":[{"id":"10.13039\/100001463","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK54053"],"award-info":[{"award-number":["DK54053"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK100592"],"award-info":[{"award-number":["DK100592"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,11]]},"abstract":"\n Significance Statement<\/jats:title>\n \n Polycystin proteins function in renal primary cilia to regulate a pathway important to kidney functional homeostasis. Autosomal dominant polycystic kidney disease (ADPKD) results when polycystin genes are mutated, but key cilia-based signaling pathways dysregulated by loss of polycystin function require elucidation. One cilia-dependent pathway suggested as playing a role in polycystic kidney diseases is the Hedgehog pathway, which is important in development, cancer, and ciliopathies. In mouse models of ADPKD, the authors used conditional control of gene expression to upregulate or inactivate Hedgehog in kidney cells that had undergone inactivation of\n Pkd1<\/jats:italic>\n , the gene encoding Polycystin-1. They found that the Hedgehog pathway had no significant effect on polycystic kidney disease initiated by\n Pkd1<\/jats:italic>\n inactivation, excluding it as a functional cell-autonomous component of kidney cyst formation in these ADPKD models.\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n PKD1<\/jats:italic>\n or\n PKD2<\/jats:italic>\n , the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n To examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation\n in vivo<\/jats:italic>\n in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of\n Pkd1<\/jats:italic>\n combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in\n Pkd1<\/jats:italic>\n initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of\n Pkd1<\/jats:italic>\n , we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We found that in\n Pkd1<\/jats:italic>\n conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n These data suggest that loss of\n Pkd1<\/jats:italic>\n function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2018121274","type":"journal-article","created":{"date-parts":[[2019,8,26]],"date-time":"2019-08-26T15:34:01Z","timestamp":1566833641000},"page":"2103-2111","source":"Crossref","is-referenced-by-count":32,"title":["Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease"],"prefix":"10.1681","volume":"30","author":[{"given":"Ming","family":"Ma","sequence":"first","affiliation":[{"name":"Internal Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Legu\u00e9","sequence":"additional","affiliation":[{"name":"Pediatrics, and"},{"name":"Vertebrate Developmental Biology Program, Yale University, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Tian","sequence":"additional","affiliation":[{"name":"Internal Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Somlo","sequence":"additional","affiliation":[{"name":"Internal Medicine,"},{"name":"Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel F.","family":"Liem","sequence":"additional","affiliation":[{"name":"Pediatrics, and"},{"name":"Vertebrate Developmental Biology Program, Yale University, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,8,26]]},"reference":[{"key":"B1-20230819","first-page":"725","article-title":"The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium.","volume":"78","year":"1994","journal-title":"Cell"},{"key":"B2-20230819","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1126\/science.272.5266.1339","article-title":"PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.","volume":"272","author":"Mochizuki","year":"1996","journal-title":"Science"},{"key":"B3-20230819","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/ng0697-179","article-title":"PKD1 interacts with PKD2 through a probable coiled-coil domain.","volume":"16","author":"Qian","year":"1997","journal-title":"Nat Genet"},{"key":"B4-20230819","doi-asserted-by":"crossref","DOI":"10.1126\/science.aat9819","article-title":"Structure of the human PKD1-PKD2 complex.","volume":"361","author":"Su","year":"2018","journal-title":"Science"},{"key":"B5-20230819","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1242\/jcs.02818","article-title":"Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif.","volume":"119","author":"Geng","year":"2006","journal-title":"J Cell Sci"},{"key":"B6-20230819","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1111\/tra.12612","article-title":"Newly synthesized polycystin-1 takes different trafficking pathways to the apical and ciliary membranes.","volume":"19","author":"Gilder","year":"2018","journal-title":"Traffic"},{"key":"B7-20230819","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/978-3-319-51436-9_11","article-title":"Primary cilia in cystic kidney disease.","volume":"60","author":"Avasthi","year":"2017","journal-title":"Results Probl Cell Differ"},{"key":"B8-20230819","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1056\/NEJMra1010172","article-title":"Ciliopathies.","volume":"364","author":"Hildebrandt","year":"2011","journal-title":"N Engl J Med"},{"key":"B9-20230819","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.cub.2007.08.034","article-title":"Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease.","volume":"17","author":"Davenport","year":"2007","journal-title":"Curr Biol"},{"key":"B10-20230819","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1681\/ASN.2011080829","article-title":"Disruption of IFT complex A causes cystic kidneys without mitotic spindle misorientation.","volume":"23","author":"Jonassen","year":"2012","journal-title":"J Am Soc Nephrol"},{"key":"B11-20230819","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.cub.2019.01.054","article-title":"Tulp3 is a ciliary trafficking gene that regulates polycystic kidney disease.","volume":"29","author":"Legu\u00e9","year":"2019","journal-title":"Curr Biol"},{"key":"B12-20230819","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nrg2774","article-title":"The primary cilium: A signalling centre during vertebrate development.","volume":"11","author":"Goetz","year":"2010","journal-title":"Nat Rev Genet"},{"key":"B13-20230819","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1038\/nature04117","article-title":"Vertebrate Smoothened functions at the primary cilium.","volume":"437","author":"Corbit","year":"2005","journal-title":"Nature"},{"key":"B14-20230819","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1126\/science.1139740","article-title":"Patched1 regulates hedgehog signaling at the primary cilium.","volume":"317","author":"Rohatgi","year":"2007","journal-title":"Science"},{"key":"B15-20230819","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.devcel.2016.07.026","article-title":"Hedgehog signal transduction: Key players, oncogenic drivers, and cancer therapy.","volume":"38","author":"Pak","year":"2016","journal-title":"Dev Cell"},{"key":"B16-20230819","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1242\/dev.02169","article-title":"Signaling from Smo to ci\/gli: Conservation and divergence of Hedgehog pathways from Drosophila to vertebrates.","volume":"133","author":"Huangfu","year":"2006","journal-title":"Development"},{"key":"B17-20230819","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0091-679X(08)94010-3","article-title":"The primary cilium as a Hedgehog signal transduction machine.","volume":"94","author":"Goetz","year":"2009","journal-title":"Methods Cell Biol"},{"key":"B18-20230819","doi-asserted-by":"crossref","first-page":"4985","DOI":"10.1038\/s41598-018-23341-2","article-title":"Inhibition of Hedgehog signaling suppresses proliferation and microcyst formation of human Autosomal Dominant Polycystic Kidney Disease cells.","volume":"8","author":"Silva","year":"2018","journal-title":"Sci Rep"},{"key":"B19-20230819","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1681\/ASN.2013070735","article-title":"Downregulating hedgehog signaling reduces renal cystogenic potential of mouse models.","volume":"25","author":"Tran","year":"2014","journal-title":"J Am Soc Nephrol"},{"key":"B20-20230819","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1038\/ng.2715","article-title":"Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease.","volume":"45","author":"Ma","year":"2013","journal-title":"Nat Genet"},{"key":"B21-20230819","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a028209","article-title":"Ciliary mechanisms of cyst formation in polycystic kidney disease.","volume":"9","author":"Ma","year":"2017","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B22-20230819","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1093\/hmg\/ddp113","article-title":"Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling.","volume":"18","author":"Norman","year":"2009","journal-title":"Hum Mol Genet"},{"key":"B23-20230819","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1093\/hmg\/ddp075","article-title":"Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: Identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway.","volume":"18","author":"Patterson","year":"2009","journal-title":"Hum Mol Genet"},{"key":"B24-20230819","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1002\/dvdy.21926","article-title":"Tulp3 is a critical repressor of mouse hedgehog signaling.","volume":"238","author":"Cameron","year":"2009","journal-title":"Dev Dyn"},{"key":"B25-20230819","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1093\/hmg\/ddn045","article-title":"Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia.","volume":"17","author":"Patel","year":"2008","journal-title":"Hum Mol Genet"},{"key":"B26-20230819","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/nm.1865","article-title":"An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice.","volume":"14","author":"Traykova-Brauch","year":"2008","journal-title":"Nat Med"},{"key":"B27-20230819","doi-asserted-by":"crossref","first-page":"10482","DOI":"10.1073\/pnas.152238499","article-title":"Early restriction of peripheral and proximal cell lineages during formation of the lung.","volume":"99","author":"Perl","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B28-20230819","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1093\/hmg\/ddn039","article-title":"Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1.","volume":"17","author":"Shibazaki","year":"2008","journal-title":"Hum Mol Genet"},{"key":"B29-20230819","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1242\/dev.128.24.5099","article-title":"Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation.","volume":"128","author":"Long","year":"2001","journal-title":"Development"},{"key":"B30-20230819","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1101\/gad.1190304","article-title":"Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia.","volume":"18","author":"Jeong","year":"2004","journal-title":"Genes Dev"},{"key":"B31-20230819","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1242\/dev.02351","article-title":"The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation.","volume":"133","author":"Corrales","year":"2006","journal-title":"Development"},{"key":"B32-20230819","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1242\/dev.015990","article-title":"Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling.","volume":"135","author":"Blaess","year":"2008","journal-title":"Development"},{"key":"B33-20230819","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/S0896-6273(03)00561-0","article-title":"Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches.","volume":"39","author":"Machold","year":"2003","journal-title":"Neuron"},{"key":"B34-20230819","first-page":"2380","article-title":"Smoothened is a master regulator of adult liver repair.","volume":"123","author":"Michelotti","year":"2013","journal-title":"J Clin Invest"},{"key":"B35-20230819","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ydbio.2008.02.026","article-title":"Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool.","volume":"317","author":"Spassky","year":"2008","journal-title":"Dev Biol"},{"key":"B36-20230819","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1136\/gutjnl-2013-305962","article-title":"Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy.","volume":"63","author":"Swiderska-Syn","year":"2014","journal-title":"Gut"},{"key":"B37-20230819","doi-asserted-by":"crossref","first-page":"5031","DOI":"10.1242\/dev.01349","article-title":"Temporal requirement for hedgehog signaling in ventral telencephalic patterning.","volume":"131","author":"Fuccillo","year":"2004","journal-title":"Development"},{"key":"B38-20230819","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/34201","article-title":"Activating Smoothened mutations in sporadic basal-cell carcinoma.","volume":"391","author":"Xie","year":"1998","journal-title":"Nature"},{"key":"B39-20230819","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1159\/000464460","article-title":"Constitutive activation of smoothened in the renal collecting ducts leads to renal hypoplasia, hydronephrosis, and hydroureter.","volume":"204","author":"Gupta","year":"2017","journal-title":"Cells Tissues Organs"},{"key":"B40-20230819","doi-asserted-by":"crossref","first-page":"11325","DOI":"10.1073\/pnas.0505328102","article-title":"Cilia and Hedgehog responsiveness in the mouse.","volume":"102","author":"Huangfu","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B41-20230819","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1038\/nm1675","article-title":"A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1.","volume":"13","author":"Piontek","year":"2007","journal-title":"Nat Med"},{"key":"B42-20230819","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1038\/nm.3314","article-title":"Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification.","volume":"19","author":"Regard","year":"2013","journal-title":"Nat Med"},{"key":"B43-20230819","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1002\/dvdy.22301","article-title":"Gli2 activator function in preosteoblasts is sufficient to mediate Ihh-dependent osteoblast differentiation, whereas the repressor function of Gli2 is dispensable for endochondral ossification.","volume":"239","author":"Kesper","year":"2010","journal-title":"Dev Dyn"},{"key":"B44-20230819","doi-asserted-by":"crossref","first-page":"e1006442","DOI":"10.1371\/journal.pgen.1006442","article-title":"Maintenance of taste organs is strictly dependent on epithelial hedgehog\/GLI signaling.","volume":"12","author":"Ermilov","year":"2016","journal-title":"PLoS Genet"},{"key":"B45-20230819","doi-asserted-by":"crossref","DOI":"10.1126\/science.aal3485","article-title":"Stromal Gli2 activity coordinates a niche signaling program for mammary epithelial stem cells.","volume":"356","author":"Zhao","year":"2017","journal-title":"Science"},{"key":"B46-20230819","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ydbio.2013.02.001","article-title":"Gli3 is required in Emx1+ progenitors for the development of the corpus callosum.","volume":"376","author":"Amaniti","year":"2013","journal-title":"Dev Biol"},{"key":"B47-20230819","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1093\/cercor\/bht244","article-title":"Expansion of the piriform cortex contributes to corticothalamic pathfinding defects in Gli3 conditional mutants.","volume":"25","author":"Amaniti","year":"2015","journal-title":"Cereb Cortex"},{"key":"B48-20230819","doi-asserted-by":"crossref","DOI":"10.1242\/dev.163147","article-title":"Gli3 controls the onset of cortical neurogenesis by regulating the radial glial cell cycle through Cdk6 expression.","volume":"145","author":"Hasenpusch-Theil","year":"2018","journal-title":"Development"},{"key":"B49-20230819","doi-asserted-by":"crossref","first-page":"6440","DOI":"10.1523\/JNEUROSCI.4892-10.2011","article-title":"Gli3 is required for maintenance and fate specification of cortical progenitors.","volume":"31","author":"Wang","year":"2011","journal-title":"J Neurosci"},{"key":"B50-20230819","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ydbio.2012.07.017","article-title":"Limb anterior-posterior polarity integrates activator and repressor functions of GLI2 as well as GLI3.","volume":"370","author":"Bowers","year":"2012","journal-title":"Dev Biol"},{"key":"B51-20230819","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S1534-5807(03)00394-0","article-title":"All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3.","volume":"6","author":"Bai","year":"2004","journal-title":"Dev Cell"},{"key":"B52-20230819","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1172\/JCI72272","article-title":"Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease.","volume":"124","author":"Harris","year":"2014","journal-title":"J Clin Invest"},{"key":"B53-20230819","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1016\/j.ajpath.2018.06.014","article-title":"Blockade of hedgehog signaling attenuates biliary cystogenesis in the polycystic kidney (PCK) rat.","volume":"188","author":"Sato","year":"2018","journal-title":"Am J Pathol"}],"container-title":["Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1681\/ASN.2018121274","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:22:09Z","timestamp":1786130529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1681\/ASN.2018121274"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,26]]},"references-count":53,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2019]]}},"URL":"https:\/\/doi.org\/10.1681\/asn.2018121274","relation":{},"ISSN":["1046-6673","1533-3450"],"issn-type":[{"value":"1046-6673","type":"print"},{"value":"1533-3450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,26]]}}}