Kidney Week

Abstract: FR-PO928

Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the GDNF-Axis in Kidney Development

Session Information

• Development, Stem Cells, Regenerative Medicine - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 501 Development, Stem Cells, and Regenerative Medicine: Basic

Authors

• Finer, Gal, Northwestern University, Chicago, Illinois, United States

Gal Finer,

• Ide, Shintaro, Chiba University Graduate School of Medicine, Chiba, Japan

Shintaro Ide,

• Souma, Tomokazu, Duke University, Durham , North Carolina, United States

Tomokazu Souma,

• Onay, Tuncer, Northwestern University, Chicago, Illinois, United States

Tuncer Onay,

• Jin, Jing, Northwestern University, Chicago, Illinois, United States

Jing Jin,

• Ye, Minghao, Northwestern University, Chicago, Illinois, United States

Minghao Ye,

• Zhao, Xiangmin, Northwestern University, Chicago, Illinois, United States

Xiangmin Zhao,

• Maezawa, Yoshiro, Chiba University Graduate School of Medicine, Chiba, Japan

Yoshiro Maezawa,

• Quaggin, Susan E., Northwestern University, Chicago, Illinois, United States

Susan E. Quaggin,

Background

The definitive mammalian kidney develops through reciprocal inductive signals between the metanephric mesenchyme (MM) and ureteric bud (UB). Transcription factor 21 (Tcf21) is highly expressed in cells of the MM including Six2+ condensing mesenchyme (CM) and Foxd1+ stromal mesenchyme (SM). Tcf21 knockout (KO) mice die in the perinatal period with severe renal hypodysplasia. In humans, Tcf21 levels are reduced in renal tissue from stillborn infants with renal dysplasia. However, molecular mechanism(s) to explain these renal defects are not yet known.

Methods

We utilized systemic and conditional Tcf21 knockout mouse models and employed immunohistochemistry, in-situ hybridization, RT qPCR and kidney explant studies.

Results

Tcf21 null kidneys show very abnormal UB branching and arrested mesenchymal-to-epithelial transition, reminiscent of human CAKUT. These changes are accompanied by decrease in Gdnf mRNA levels and protein and by low Ret and Wnt11 mRNA levels starting at embryonic day (E)12.5. In contrast, global deletion of Tcf21 does not attenuate the expression of members of the retioic acid and fibroblast growth factor signaling pathways, nor does it reduce expression of inducers of Gdnf (e.g. Osr1, Eya1, and Pax2). The stromal factor Bmp4, a potent inhibitor of Gdnf, is increased in kidneys from Tcf21 KO mice, offering a potential mechanism. Under the hypothesis of pleiotropism, we dissociated Tcf21's effects in distinct cell lineages of the MM by studying the kidney phenotype of selective removal of Tcf21 from the renal stroma (Tcf21^fl/fl;FoxD1-Cre strain) and from the CM (Tcf21^fl/fl;Six2-Cre strain). Absence of Tcf21 from the stroma leads to low Gdnf and abnormal UB branching at E14.5 and results in paucity of collecting ducts and severe urinary concentrating defect at 4 wks of life. In contrast, deletion of Tcf21 from the CM leads to abnormal glomerulogenesis and proteinuria but has no obvious effects on Gdnf expression or the development of the collecting ducts.

Conclusion

Taken together, our data illustrate distinct roles of Tcf21 in the stromal mesenchyme and cap mesenchyme in kidney development and support a model whereby Tcf21 regulates key molecular pathways required for branching morphogenesis. Direct genetic targets for Tcf21 in the kidney have not yet identified.

Funding

• Other U.S. Government Support