--- _id: '1488' abstract: - lang: eng text: Branching morphogenesis of the epithelial ureteric bud forms the renal collecting duct system and is critical for normal nephron number, while low nephron number is implicated in hypertension and renal disease. Ureteric bud growth and branching requires GDNF signaling from the surrounding mesenchyme to cells at the ureteric bud tips, via the Ret receptor tyrosine kinase and coreceptor Gfrα1; Ret signaling up-regulates transcription factors Etv4 and Etv5, which are also critical for branching. Despite extensive knowledge of the genetic control of these events, it is not understood, at the cellular level, how renal branching morphogenesis is achieved or how Ret signaling influences epithelial cell behaviors to promote this process. Analysis of chimeric embryos previously suggested a role for Ret signaling in promoting cell rearrangements in the nephric duct, but this method was unsuited to study individual cell behaviors during ureteric bud branching. Here, we use Mosaic Analysis with Double Markers (MADM), combined with organ culture and time-lapse imaging, to trace the movements and divisions of individual ureteric bud tip cells. We first examine wild-type clones and then Ret or Etv4 mutant/wild-type clones in which the mutant and wild-type sister cells are differentially and heritably marked by green and red fluorescent proteins. We find that, in normal kidneys, most individual tip cells behave as self-renewing progenitors, some of whose progeny remain at the tips while others populate the growing UB trunks. In Ret or Etv4 MADM clones, the wild-type cells generated at a UB tip are much more likely to remain at, or move to, the new tips during branching and elongation, while their Ret−/− or Etv4−/− sister cells tend to lag behind and contribute only to the trunks. By tracking successive mitoses in a cell lineage, we find that Ret signaling has little effect on proliferation, in contrast to its effects on cell movement. Our results show that Ret/Etv4 signaling promotes directed cell movements in the ureteric bud tips, and suggest a model in which these cell movements mediate branching morphogenesis. acknowledgement: We thank Silvia Arber, Thomas Jessell, Kenneth M. Murphy, Carlton Bates, Hideki Enomoto, Liqun Luo and Andrew McMahon for mouse strains; Thomas Jessell for antibodies; and Laura Martinez Prat for experimental assistance. article_number: e1002382 article_processing_charge: No author: - first_name: Paul full_name: Riccio, Paul last_name: Riccio - first_name: Cristina full_name: Cebrián, Cristina last_name: Cebrián - first_name: Hui full_name: Zong, Hui last_name: Zong - first_name: Simon full_name: Hippenmeyer, Simon id: 37B36620-F248-11E8-B48F-1D18A9856A87 last_name: Hippenmeyer orcid: 0000-0003-2279-1061 - first_name: Frank full_name: Costantini, Frank last_name: Costantini citation: ama: Riccio P, Cebrián C, Zong H, Hippenmeyer S, Costantini F. Ret and Etv4 promote directed movements of progenitor cells during renal branching morphogenesis. PLoS Biology. 2016;14(2). doi:10.1371/journal.pbio.1002382 apa: Riccio, P., Cebrián, C., Zong, H., Hippenmeyer, S., & Costantini, F. (2016). Ret and Etv4 promote directed movements of progenitor cells during renal branching morphogenesis. PLoS Biology. Public Library of Science. https://doi.org/10.1371/journal.pbio.1002382 chicago: Riccio, Paul, Cristina Cebrián, Hui Zong, Simon Hippenmeyer, and Frank Costantini. “Ret and Etv4 Promote Directed Movements of Progenitor Cells during Renal Branching Morphogenesis.” PLoS Biology. Public Library of Science, 2016. https://doi.org/10.1371/journal.pbio.1002382. ieee: P. Riccio, C. Cebrián, H. Zong, S. Hippenmeyer, and F. Costantini, “Ret and Etv4 promote directed movements of progenitor cells during renal branching morphogenesis,” PLoS Biology, vol. 14, no. 2. Public Library of Science, 2016. ista: Riccio P, Cebrián C, Zong H, Hippenmeyer S, Costantini F. 2016. Ret and Etv4 promote directed movements of progenitor cells during renal branching morphogenesis. PLoS Biology. 14(2), e1002382. mla: Riccio, Paul, et al. “Ret and Etv4 Promote Directed Movements of Progenitor Cells during Renal Branching Morphogenesis.” PLoS Biology, vol. 14, no. 2, e1002382, Public Library of Science, 2016, doi:10.1371/journal.pbio.1002382. short: P. Riccio, C. Cebrián, H. Zong, S. Hippenmeyer, F. Costantini, PLoS Biology 14 (2016). date_created: 2018-12-11T11:52:19Z date_published: 2016-02-19T00:00:00Z date_updated: 2025-09-18T11:28:32Z day: '19' ddc: - '570' department: - _id: SiHi doi: 10.1371/journal.pbio.1002382 external_id: isi: - '000371883600013' file: - access_level: open_access checksum: 7f8fa1b3a29f94c0a14dd4465278cdbc content_type: application/pdf creator: system date_created: 2018-12-12T10:13:42Z date_updated: 2020-07-14T12:44:57Z file_id: '5027' file_name: IST-2016-517-v1+1_journal.pbio.1002382_1_.PDF file_size: 5904773 relation: main_file file_date_updated: 2020-07-14T12:44:57Z has_accepted_license: '1' intvolume: ' 14' isi: 1 issue: '2' language: - iso: eng license: https://creativecommons.org/licenses/by/4.0/ month: '02' oa: 1 oa_version: Published Version publication: PLoS Biology publication_status: published publisher: Public Library of Science publist_id: '5699' pubrep_id: '517' quality_controlled: '1' related_material: record: - id: '9703' relation: research_data status: deleted scopus_import: '1' status: public title: Ret and Etv4 promote directed movements of progenitor cells during renal branching morphogenesis tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345 volume: 14 year: '2016' ...