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However, bladder development and its\u2019 embryonic function remain poorly understood. Here, we report that in both humans and mice the bladder emerges from the cloaca as the rostral outgrowth, which is flanked by the umbilical arteries. Arrest of the outgrowth, as seen in\n                  <jats:italic>Shh-<\/jats:italic>\n                  null mouse embryos, causes bladder agenesis and unexpected severe defect of the umbilical arteries, suggesting that the outgrowth epithelial signal\n                  <jats:italic>Shh<\/jats:italic>\n                  coordinates development of both the bladder and umbilical arteries.\n                  <jats:italic>Wnt2<\/jats:italic>\n                  signaling molecule is restricted to the rostral outgrowth mesenchyme; and its\u2019 expression is dramatically down-regulated in\n                  <jats:italic>Shh-<\/jats:italic>\n                  null mutants. Furthermore,\n                  <jats:italic>Wnt2-<\/jats:italic>\n                  null mutants develop small bladder and single umbilical artery defects. Findings here uncover an unexpected co-development mechanism of the bladder and umbilical arteries orchestrated by the cloacal outgrowth signals. The co-development paradigm offers a conceptual framework to understand evolution and development of the bladder.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    The urinary bladder is found in the eutherian mammals but largely absent from other vertebrates. Innovation of the bladder has been viewed as a necessity to manage liquid metabolic wastes on dry land. In this study, we report that the bladder emerges from the rostral outgrowth of the cloaca. We also report an unexpected developmental link between the bladder and umbilical arteries and, demonstrate that their co-development is orchestrated by the outgrowth epithelial signal\n                    <jats:italic>Shh<\/jats:italic>\n                    and mesenchymal signal\n                    <jats:italic>Wnt2<\/jats:italic>\n                    . Findings here highlight a possibility that, in addition to managing metabolic wastes, normal bladder development is required for growth of mammalian embryos by supporting development of the umbilical arteries.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.18.689093","type":"posted-content","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:15:12Z","timestamp":1763532912000},"source":"Crossref","is-referenced-by-count":0,"title":["The cloacal outgrowth orchestrates co-development of the bladder and umbilical arteries"],"prefix":"10.64898","author":[{"given":"Xing","family":"Ye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liguang","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianfa","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruirong","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haochuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingsheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Morrisey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongrong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naihe","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3072-0573","authenticated-orcid":false,"given":"Xue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025112103201191000_2025.11.18.689093v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-185X.1975.tb01057.x"},{"issue":"6","key":"2025112103201191000_2025.11.18.689093v1.2","first-page":"563","article-title":"The vertebrate urinary bladder: osmoregulatory and other uses","volume":"52","year":"1979","journal-title":"Yale J Biol Med"},{"issue":"12","key":"2025112103201191000_2025.11.18.689093v1.3","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1007\/s42452-019-1692-9","article-title":"The evolution of the urinary bladder as a storage organ: scent trails and selective pressure of the first land animals in a computational simulation","volume":"1","year":"2019","journal-title":"SN Applied Sciences"},{"key":"2025112103201191000_2025.11.18.689093v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.1212"},{"key":"2025112103201191000_2025.11.18.689093v1.5","doi-asserted-by":"publisher","DOI":"10.1242\/dev.117903"},{"key":"2025112103201191000_2025.11.18.689093v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2015.10.018"},{"issue":"6","key":"2025112103201191000_2025.11.18.689093v1.7","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1111\/joa.12882","article-title":"The development of the cloaca in the human embryo","volume":"233","year":"2018","journal-title":"J Anat"},{"key":"2025112103201191000_2025.11.18.689093v1.8","doi-asserted-by":"crossref","unstructured":"de Bakker BS , de Jong KH , Hagoort J , de Bree K , Besselink CT , de Kanter FE , et al. 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