Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts
- Columbia University, United States
- Max Delbruck Center for Molecular Medicine, Germany
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
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Identification of Tfcp2l1 target genes in the mouse kidneyPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE87769).
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Tfcp2l1 controls cellular patterning of the collecting duct.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE85325).
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RNA-Seq Gene Expression Analysis in Rat Metanephric Mesenchyme overexpressing Transcription Factor Tfcp2l1Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE87744).
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Genome wide map of Tfcp2l1 binding sites from mouse kidneyPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE87752).
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Mapping of transcription factor binding sites in mouse embryonic stem cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE11431).
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Gene expression in epithelial and non-epithelial cells of renal originPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE24295).
Article and author information
Author details
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
- Roy Zent, Vanderbilt University Medical Center, United States
Publication history
- Received: December 19, 2016
- Accepted: June 3, 2017
- Accepted Manuscript published: June 3, 2017 (version 1)
- Accepted Manuscript updated: June 13, 2017 (version 2)
- Version of Record published: June 26, 2017 (version 3)
- 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.
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Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts
eLife 6:e24265.
https://doi.org/10.7554/eLife.24265
Further reading
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- Cell Biology
In the adult Drosophila midgut, basal intestinal stem cells give rise to enteroblasts that integrate into the epithelium as they differentiate into enterocytes. Integrating enteroblasts must generate a new apical domain and break through the septate junctions between neighbouring enterocytes, while maintaining barrier function. We observe that enteroblasts form an apical membrane initiation site (AMIS) when they reach the septate junction between the enterocytes. Cadherin clears from the apical surface and an apical space appears between above the enteroblast. New septate junctions then form laterally with the enterocytes and the AMIS develops into an apical domain below the enterocyte septate junction. The enteroblast therefore forms a pre-assembled apical compartment before it has a free apical surface in contact with the gut lumen. Finally, the enterocyte septate junction disassembles and the enteroblast/pre-enterocyte reaches the gut lumen with a fully-formed brush border. The process of enteroblast integration resembles lumen formation in mammalian epithelial cysts, highlighting the similarities between the fly midgut and mammalian epithelia.
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- Cell Biology
- Genetics and Genomics
Major genomic deletions in independent eukaryotic lineages have led to repeated ancestral loss of biosynthesis pathways for nine of the twenty canonical amino acids1. While the evolutionary forces driving these polyphyletic deletion events are not well understood, the consequence is that extant metazoans are unable to produce nine essential amino acids (EAAs). Previous studies have highlighted that EAA biosynthesis tends to be more energetically costly2,3, raising the possibility that these pathways were lost from organisms with access to abundant EAAs in the environment4,5. It is unclear whether present-day metazoans can reaccept these pathways to resurrect biosynthetic capabilities that were lost long ago or whether evolution has rendered EAA pathways incompatible with metazoan metabolism. Here, we report progress on a large-scale synthetic genomics effort to reestablish EAA biosynthetic functionality in mammalian cells. We designed codon-optimized biosynthesis pathways based on genes mined from Escherichia coli. These pathways were de novo synthesized in 3 kilobase chunks, assembled in yeasto and genomically integrated into a Chinese Hamster Ovary (CHO) cell line. One synthetic pathway produced valine at a sufficient level for cell viability and proliferation, and thus represents a successful example of metazoan EAA biosynthesis restoration. This prototrophic CHO line grows in valine-free medium, and metabolomics using labeled precursors verified de novo biosynthesis of valine. RNA-seq profiling of the valine prototrophic CHO line showed that the synthetic pathway minimally disrupted the cellular transcriptome. Furthermore, valine prototrophic cells exhibited transcriptional signatures associated with rescue from nutritional starvation. 13C-tracing revealed build-up of pathway intermediate 2,3-dihydroxy-3-isovalerate in these cells. Increasing the dosage of downstream ilvD boosted pathway performance and allowed for long-term propagation of second-generation cells in valine-free medium at a consistent doubling time of 3.2 days. This work demonstrates that mammalian metabolism is amenable to restoration of ancient core pathways, paving a path for genome-scale efforts to synthetically restore metabolic functions to the metazoan lineage.
