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Updated: Feb 13, 2026

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Published on: September 13, 2011
A knock in Six2Cre line reveals transient interstitial potential in nephron progenitors
Azadeh Haghighitalab1,2, Fariba Nosrati1,2, Zeinab Dehghani-Ghobadi1,2
1Feinberg Cardiovascular & Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Abstract:
The developmental relationship between nephron progenitors and the renal interstitium remains unresolved, in part due to limitations of existing lineage tracing tools. The widely used transgenic Six2TGC line, which is routinely employed to target the nephron lineage, exhibits mosaic recombination and altered progenitor dynamics. To overcome these shortcomings, we generate a knock-in Six2Cre mouse allele that faithfully recapitulates endogenous Six2 expression, preserves nephron endowment, and achieves near-complete, non-mosaic recombination. Side-by-side lineage tracing with Six2Cre and Six2TGC, combined with RNA velocity analysis of single-cell RNA-sequencing datasets, reveals a brief interval around embryonic day 11 during which Six2-expressing mesenchymal nephron progenitors contribute to the renal interstitium. This contribution is transient and stage-restricted. These findings reveal an early dual potential within nephron progenitors and define a precise developmental window for dissecting mechanisms that coordinate nephron-interstitium integration.
Insights
A new Six2Cre mouse model accurately traces kidney development. It reveals that Six2-expressing nephron progenitors transiently contribute to the renal interstitium during a specific embryonic window.
Area of Science:
- Developmental biology
- Renal biology
- Genetics
Background:
- The developmental origins of the kidney interstitium and its relationship with nephron progenitors are unclear.
- Existing lineage tracing tools, like the Six2TGC mouse line, have limitations including mosaic recombination and altered progenitor cell dynamics.
Purpose of the Study:
- To develop a more accurate lineage tracing tool for studying kidney development.
- To investigate the contribution of Six2-expressing nephron progenitors to the renal interstitium.
Main Methods:
- Generation of a knock-in Six2Cre mouse allele to faithfully recapitulate endogenous Six2 expression.
- Side-by-side lineage tracing comparing Six2Cre and Six2TGC mouse lines.
- RNA velocity analysis of single-cell RNA-sequencing datasets.
Main Results:
- The Six2Cre allele provides near-complete, non-mosaic recombination and preserves nephron endowment.
- Six2-expressing mesenchymal nephron progenitors transiently contribute to the renal interstitium around embryonic day 11.
- This contribution is stage-restricted, indicating a brief developmental window.
Conclusions:
- Nephron progenitors exhibit transient dual potential, contributing to both nephrons and the renal interstitium.
- The study defines a precise developmental window for investigating nephron-interstitium integration mechanisms.
- The Six2Cre mouse model is a superior tool for studying kidney development.
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