Abstract: TH-OR085

Transcription Factor 21 (TCF21) Controls Branching Morphogenesis via GDNF Signaling and Has Pleiotropic Roles in Kidney Development

Session Information

Category: Developmental Biology and Inherited Kidney Diseases

  • 401 Developmental Biology


  • Finer, Gal, Northwestern University, Ann & Robert H. Lurie Children's Hospital of Chicago , Chicago, Illinois, United States
  • Ide, Shintaro, Chiba University Graduate School of Medicine, Chiba, Japan
  • Souma, Tomokazu, None, Chicago, Illinois, United States
  • Ye, Minghao, Northwestern University, Chicago, Illinois, United States
  • Jin, Jing, Northwestern University, Chicago, Illinois, United States
  • Maezawa, Yoshiro, Chiba University Graduate School of Medicine, Chiba, Japan
  • Quaggin, Susan E., Northwestern University, Chicago, Illinois, United States

Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of chronic kidney disease in children. Although the pathogenesis of CAKUT is incompletely understood and heterogeneous, many cases arise from alterations in genes critical for kidney development. We previously showed that absence of Tcf21 causes CAKUT in the mouse but the mechanisms remain obscure.


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


Global deletion of Tcf21 showed abnormal UB branching and arrested mesenchymal to epithelial transition with resultant severe renal dysplasia. These kidneys had markedly reduced expression of Gdnf, Wnt11 and Ret mRNA to 16%, 29% and 52% of normal levels respectively. When Tcf21 was specifically deleted from the cap mesenchyme and its progenitors (Tcf21fl/fl;Six2-Cre), mutant kidneys showed abnormal UB branching at early developmental stages (E11.5-13.5) but normal appearing collecting ducts subsequently. Importantly however, when Tcf21 was selectively deleted from kidney stromal cells (Tcf21fl/fl;FoxD1-Cre), the mice developed diabetes insipidus-like phenotype suggestive of functional defect in the collecting ducts. This was also supported by findings of severe defect in UB branching at early stages of kidney development and by the absence of collecting ducts at P0 in Tcf21fl/fl;FoxD1-Cre mice. Mechanistically, deletion of Tcf21 from renal stromal cells was again associated with down-regulation of Gdnf and Wnt11 supporting impaired branching signaling. Moreover, the stromal factor BMP4, a known inhibitor of GDNF, was up-regulated in Tcf21 null kidneys both at the mRNA and protein levels. This suggested that TCF21 controls UB branching by regulating BMP4.


Taken together, these results suggest that TCF21 is essential for normal branching morphogenesis via regulation of Gdnf-Wnt11-Ret axis, likely via control of BMP4 in the renal stroma. Further study is required to identify direct gene targets for TCF21.


  • Private Foundation Support