1. Cell Biology
  2. Developmental Biology
Download icon

Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts

  1. Max Werth
  2. Kai M Schmidt-Ott
  3. Thomas Leete
  4. Andong Qiu
  5. Christian Hinze
  6. Melanie Viltard
  7. Neal Paragas
  8. Carrie J Shawber
  9. Wenqiang Yu
  10. Peter Lee
  11. Xia Chen
  12. Abby Sarkar
  13. Weiyi Mu
  14. Alexander Rittenberg
  15. Chyuan-Sheng Lin
  16. Jan Kitajewski
  17. Qais Al-Awqati
  18. Jonathan Barasch  Is a corresponding author
  1. Columbia University, United States
  2. Max Delbruck Center for Molecular Medicine, Germany
Research Article
  • Cited 22
  • Views 2,231
  • Annotations
Cite this article as: eLife 2017;6:e24265 doi: 10.7554/eLife.24265

Abstract

Although most nephron segments contain one type of epithelial cell, the collecting ducts consists of at least two: intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. In adult kidneys, these cells are organized in rosettes suggesting functional interactions. Genetic studies in mouse revealed that transcription factor Tfcp2l1 coordinates IC and PC development. Tfcp2l1 induces the expression of IC specific genes, including specific H+-ATPase subunits and Jag1. Jag1 in turn, initiates Notch signaling in PCs but inhibits Notch signaling in ICs. Tfcp2l1 inactivation deletes ICs, whereas Jag1 inactivation results in the forfeiture of discrete IC and PC identities. Thus, Tfcp2l1 is a critical regulator of IC-PC patterning, acting cell-autonomously in ICs, and non-cell-autonomously in PCs. As a result, Tfcp2l1 regulates the diversification of cell types which is the central characteristic of 'salt and pepper' epithelia and distinguishes the collecting duct from all other nephron segments.

Article and author information

Author details

  1. Max Werth

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0169-6233

  2. Kai M Schmidt-Ott

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Thomas Leete

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Andong Qiu

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Christian Hinze

    Max Delbruck Center for Molecular Medicine, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.

  6. Melanie Viltard

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Neal Paragas

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Carrie J Shawber

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Wenqiang Yu

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Peter Lee

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Xia Chen

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Abby Sarkar

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  13. Weiyi Mu

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  14. Alexander Rittenberg

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  15. Chyuan-Sheng Lin

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  16. Jan Kitajewski

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  17. Qais Al-Awqati

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7141-1040

  18. Jonathan Barasch

    Columbia University, New York, United States
    For correspondence
    jmb4@columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6723-9548

Funding

National Institutes of Health (RO1DK073462)

  • Jonathan Barasch

March of Dimes Foundation (Research Grant)

  • Jonathan Barasch

National Institutes of Health (RO1DK092684)

  • Jonathan Barasch

National Institutes of Health (U54DK104309)

  • Jonathan Barasch

Deutsche Forschungsgemeinschaft (FOR 1368 FOR667 Emmy Noether)

  • Kai M Schmidt-Ott

Urological Research Foundation Berlin

  • Kai M Schmidt-Ott

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were approved by the Institutional Animal Care and Use Committee (IACUC) at Columbia. Protocol # AC-AAAH7404.

Reviewing Editor

  1. Roy Zent, Vanderbilt University Medical Center, United States

Publication history

  1. Received: December 19, 2016
  2. Accepted: June 3, 2017
  3. Accepted Manuscript published: June 3, 2017 (version 1)
  4. Accepted Manuscript updated: June 13, 2017 (version 2)
  5. Version of Record published: June 26, 2017 (version 3)
  6. Version of Record updated: June 27, 2017 (version 4)

Copyright

© 2017, Werth et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,231
    Page views
  • 395
    Downloads
  • 22
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Cell Biology

    Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes

    Shima Ghoroghi et al.
    Research Article Updated

    Cancer extracellular vesicles (EVs) shuttle at distance and fertilize pre-metastatic niches facilitating subsequent seeding by tumor cells. However, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Using mouse models, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and tune the biogenesis and secretion of pro-metastatic EVs. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivoand are less efficient in promoting metastasis. RalA and RalB reduce the EV levels of the adhesion molecule MCAM/CD146, which favors EV-mediated metastasis by allowing EVs targeting to the lungs. Finally, RalA, RalB, and MCAM/CD146, are factors of poor prognosis in breast cancer patients. Altogether, our study identifies RalGTPases as central molecules linking the mechanisms of EVs secretion and cargo loading to their capacity to disseminate and induce pre-metastatic niches in a CD146-dependent manner.

    1. Cell Biology

    Optogenetic control of PRC1 reveals its role in chromosome alignment on the spindle by overlap length-dependent forces

    Mihaela Jagrić et al.
    Research Article

    During metaphase, chromosome position at the spindle equator is regulated by the forces exerted by kinetochore microtubules and polar ejection forces. However, the role of forces arising from mechanical coupling of sister kinetochore fibers with bridging fibers in chromosome alignment is unknown. Here we develop an optogenetic approach for acute removal of PRC1 to partially disassemble bridging fibers and show that they promote chromosome alignment. Tracking of the plus-end protein EB3 revealed longer antiparallel overlaps of bridging microtubules upon PRC1 removal, which was accompanied by misaligned and lagging kinetochores. Kif4A/kinesin-4 and Kif18A/kinesin-8 were found within the bridging fiber and largely lost upon PRC1 removal, suggesting that these proteins regulate the overlap length of bridging microtubules. We propose that PRC1-mediated crosslinking of bridging microtubules and recruitment of kinesins to the bridging fiber promotes chromosome alignment by overlap length-dependent forces transmitted to the associated kinetochore fibers.

    1. Cell Biology

    Cross-compartment signal propagation in the mitotic exit network

    Xiaoxue Zhou et al.
    Research Article

    In budding yeast, the mitotic exit network (MEN), a GTPase signaling cascade, integrates spatial and temporal cues to promote exit from mitosis. This signal integration requires transmission of a signal generated on the cytoplasmic face of spindle pole bodies (SPBs; yeast equivalent of centrosomes) to the nucleolus, where the MEN effector protein Cdc14 resides. Here, we show that the MEN activating signal at SPBs is relayed to Cdc14 in the nucleolus through the dynamic localization of its terminal kinase complex Dbf2-Mob1. Cdc15, the protein kinase that activates Dbf2-Mob1 at SPBs, also regulates its nuclear access. Once in the nucleus, priming phosphorylation of Cfi1/Net1, the nucleolar anchor of Cdc14, by the Polo-like kinase Cdc5 targets Dbf2-Mob1 to the nucleolus. Nucleolar Dbf2-Mob1 then phosphorylates Cfi1/Net1 and Cdc14, activating Cdc14. The kinase-primed transmission of the MEN signal from the cytoplasm to the nucleolus exemplifies how signaling cascades can bridge distant inputs and responses.