{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T14:54:36Z","timestamp":1782312876332,"version":"3.54.5"},"posted":{"date-parts":[[2025,11,21]]},"group-title":"Genetics","reference-count":81,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH","award":["R01DK128902"],"award-info":[{"award-number":["R01DK128902"]}]},{"name":"NIH","award":["R35GM148416"],"award-info":[{"award-number":["R35GM148416"]}]},{"name":"NIH","award":["R25DK101390"],"award-info":[{"award-number":["R25DK101390"]}]},{"name":"NIH","award":["K12GM000680"],"award-info":[{"award-number":["K12GM000680"]}]},{"name":"NIH","award":["F32DK127848"],"award-info":[{"award-number":["F32DK127848"]}]},{"name":"NIH","award":["K01DK140605"],"award-info":[{"award-number":["K01DK140605"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Polycystic kidney disease (PKD) is the leading genetic cause of renal failure, resulting in the accumulation of fluid filled cysts and gross enlargement of the kidney. Mutations in\n                    <jats:italic>PKD1<\/jats:italic>\n                    or\n                    <jats:italic>PKD2<\/jats:italic>\n                    , which encode ciliary polycystin proteins, are the most common cause of PKD. These proteins function in a cilia-dependent cyst activation (CDCA) pathway\u2013one that requires cilia for its pro-cystic function\u2013yet the molecular driver(s) of this pathway are unknown. ARL13B is a regulatory GTPase enriched in cilia and links to renal cystogenesis. ARL13B possesses guanine nucleotide exchange factor (GEF) activity for ARL3, another ARL with links to cilia.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We used two distinct\n                    <jats:italic>Arl13b<\/jats:italic>\n                    mouse alleles to investigate whether ARL13B is a component of the CDCA pathway:\n                    <jats:italic>\n                      Arl13b\n                      <jats:sup>V358A<\/jats:sup>\n                    <\/jats:italic>\n                    encodes for enzymatically normal ARL13B that is undetectable in cilia, and\n                    <jats:italic>\n                      Arl13b\n                      <jats:sup>R79Q<\/jats:sup>\n                    <\/jats:italic>\n                    encodes for cilia-localized ARL13B lacking a residue critical for its ARL3 GEF activity. We used these alleles in a\n                    <jats:italic>Pkd1<\/jats:italic>\n                    -deficient adult mouse model and investigated renal morphology (H&amp;E and cystic index analysis), physiology (blood urea nitrogen measurements), renal fibrosis (picrosirius staining and \u03b1-smooth muscle actin levels), renal injury (SOX9 immunofluorescent staining and quantification), and Wnt signaling (\u03b2-catenin and cyclin D1 protein levels).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We found that loss of ciliary ARL13B or mutation of a single residue critical for its ARL3 GEF activity suppressed\n                    <jats:italic>Pkd1<\/jats:italic>\n                    -dependent cysts. We observed reductions in kidney size, cystic index, and blood urea nitrogen. We also observed suppression of renal fibrosis, renal injury, and \u03b2-catenin and cyclin D1 protein levels.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Our results identified a subcellular location and mechanism driving\n                    <jats:italic>Pkd1<\/jats:italic>\n                    -dependent renal cystogenesis. We demonstrated that expression of a critical residue for ARL13B\u2019s GEF activity specifically in cilia is a key mechanism of the CDCA pathway driving renal cystogenesis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Loss of ciliary ARL13B suppressed renal cystogenesis in an adult mouse model of polycystic kidney disease (PKD) without ablating cilia<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Loss of ciliary ARL13B or mutation of the residue critical for its GEF activity did not affect renal morphology or physiology in an adult induced mouse model<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Mutation of a residue critical for ARL13B activation of ARL3 suppressed cystic phenotypes in\n                        <jats:italic>Pkd1<\/jats:italic>\n                        -dependent cysts\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.20.689124","type":"posted-content","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T22:10:18Z","timestamp":1763763018000},"source":"Crossref","is-referenced-by-count":0,"title":["Ciliary ARL13B drives renal cystogenesis via its GEF activity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1818-2661","authenticated-orcid":false,"given":"Robert E.","family":"Van Sciver","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA 30322, USA"},{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham Heersink School of Medicine, 1918 University Boulevard, McCallum 227, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3037-2059","authenticated-orcid":false,"given":"Avery","family":"Forster","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA 30322, USA"},{"name":"Dana-Farber Cancer Institute, 375 Longwood Ave, LW-745, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7522-3397","authenticated-orcid":false,"given":"Leslie M.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham Heersink School of Medicine, 1918 University Boulevard, McCallum 227, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6579-7589","authenticated-orcid":false,"given":"Tamara","family":"Caspary","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026062407350870000_2025.11.20.689124v4.1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1159\/000494923","article-title":"Analysis of Nationwide Data to Determine the Incidence and Diagnosed Prevalence of Autosomal Dominant Polycystic Kidney Disease in the USA: 2013\u20132015","volume":"5","year":"2019","journal-title":"Kidney Diseases"},{"key":"2026062407350870000_2025.11.20.689124v4.2","first-page":"1356","article-title":"Prevalence of autosomal dominant polycystic kidney disease in the European Union","volume":"32","year":"2016","journal-title":"Nephrology Dialysis Transplantation"},{"key":"2026062407350870000_2025.11.20.689124v4.3","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41572-018-0047-y","article-title":"Polycystic kidney disease","volume":"4","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"2026062407350870000_2025.11.20.689124v4.4","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018050493"},{"key":"2026062407350870000_2025.11.20.689124v4.5","doi-asserted-by":"crossref","unstructured":"Lanktree, M.B. , Haghighi, A. , di Bari, I. , Song, X. & Pei, Y . 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