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.

Data availability

The following data sets were generated
    1. Werth et al.
    (2017) Identification of Tfcp2l1 target genes in the mouse kidney
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE87769).
    1. Werth M
    2. Barasch J
    (2017) Tfcp2l1 controls cellular patterning of the collecting duct.
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE85325).
    1. Werth M
    2. Barasch J
    (2017) Genome wide map of Tfcp2l1 binding sites from mouse kidney
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE87752).
The following previously published data sets were used

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.

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

  • 3,246
    views
  • 512
    downloads
  • 64
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  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
(2017)
Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts
eLife 6:e24265.
https://doi.org/10.7554/eLife.24265

Share this article

https://doi.org/10.7554/eLife.24265

Further reading

    1. Cell Biology
    Tomoharu Kanie, Roy Ng ... Peter K Jackson
    Research Article

    The primary cilium is a microtubule-based organelle that cycles through assembly and disassembly. In many cell types, formation of the cilium is initiated by recruitment of ciliary vesicles to the distal appendage of the mother centriole. However, the distal appendage mechanism that directly captures ciliary vesicles is yet to be identified. In an accompanying paper, we show that the distal appendage protein, CEP89, is important for the ciliary vesicle recruitment, but not for other steps of cilium formation (Tomoharu Kanie, Love, Fisher, Gustavsson, & Jackson, 2023). The lack of a membrane binding motif in CEP89 suggests that it may indirectly recruit ciliary vesicles via another binding partner. Here, we identify Neuronal Calcium Sensor-1 (NCS1) as a stoichiometric interactor of CEP89. NCS1 localizes to the position between CEP89 and a ciliary vesicle marker, RAB34, at the distal appendage. This localization was completely abolished in CEP89 knockouts, suggesting that CEP89 recruits NCS1 to the distal appendage. Similarly to CEP89 knockouts, ciliary vesicle recruitment as well as subsequent cilium formation was perturbed in NCS1 knockout cells. The ability of NCS1 to recruit the ciliary vesicle is dependent on its myristoylation motif and NCS1 knockout cells expressing a myristoylation defective mutant failed to rescue the vesicle recruitment defect despite localizing properly to the centriole. In sum, our analysis reveals the first known mechanism for how the distal appendage recruits the ciliary vesicles.

    1. Cell Biology
    Tomoharu Kanie, Beibei Liu ... Peter K Jackson
    Research Article

    Distal appendages are nine-fold symmetric blade-like structures attached to the distal end of the mother centriole. These structures are critical for formation of the primary cilium, by regulating at least four critical steps: ciliary vesicle recruitment, recruitment and initiation of intraflagellar transport (IFT), and removal of CP110. While specific proteins that localize to the distal appendages have been identified, how exactly each protein functions to achieve the multiple roles of the distal appendages is poorly understood. Here we comprehensively analyze known and newly discovered distal appendage proteins (CEP83, SCLT1, CEP164, TTBK2, FBF1, CEP89, KIZ, ANKRD26, PIDD1, LRRC45, NCS1, CEP15) for their precise localization, order of recruitment, and their roles in each step of cilia formation. Using CRISPR-Cas9 knockouts, we show that the order of the recruitment of the distal appendage proteins is highly interconnected and a more complex hierarchy. Our analysis highlights two protein modules, CEP83-SCLT1 and CEP164-TTBK2, as critical for structural assembly of distal appendages. Functional assays revealed that CEP89 selectively functions in RAB34+ ciliary vesicle recruitment, while deletion of the integral components, CEP83-SCLT1-CEP164-TTBK2, severely compromised all four steps of cilium formation. Collectively, our analyses provide a more comprehensive view of the organization and the function of the distal appendage, paving the way for molecular understanding of ciliary assembly.