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.

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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