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

J Am Soc Nephrol. 2018 Dec;29(12):2795-2808. doi: 10.1681/ASN.2017121278. Epub 2018 Oct 30.

Abstract

Background: The mammalian kidney develops through reciprocal inductive signals between the metanephric mesenchyme and ureteric bud. Transcription factor 21 (Tcf21) is highly expressed in the metanephric mesenchyme, including Six2-expressing cap mesenchyme and Foxd1-expressing stromal mesenchyme. Tcf21 knockout mice die in the perinatal period from severe renal hypodysplasia. In humans, Tcf21 mRNA levels are reduced in renal tissue from human fetuses with renal dysplasia. The molecular mechanisms underlying these renal defects are not yet known.

Methods: Using a variety of techniques to assess kidney development and gene expression, we compared the phenotypes of wild-type mice, mice with germline deletion of the Tcf21 gene, mice with stromal mesenchyme-specific Tcf21 deletion, and mice with cap mesenchyme-specific Tcf21 deletion.

Results: Germline deletion of Tcf21 leads to impaired ureteric bud branching and is accompanied by downregulated expression of Gdnf-Ret-Wnt11, a key pathway required for branching morphogenesis. Selective removal of Tcf21 from the renal stroma is also associated with attenuation of the Gdnf signaling axis and leads to a defect in ureteric bud branching, a paucity of collecting ducts, and a defect in urine concentration capacity. In contrast, deletion of Tcf21 from the cap mesenchyme leads to abnormal glomerulogenesis and massive proteinuria, but no downregulation of Gdnf-Ret-Wnt11 or obvious defect in branching.

Conclusions: Our findings indicate that Tcf21 has distinct roles in the cap mesenchyme and stromal mesenchyme compartments during kidney development and suggest that Tcf21 regulates key molecular pathways required for branching morphogenesis.

Keywords: Congenital Anomalies of the Kidney and Urinary Tract; Metanephric mesenchyme; Renal stroma; Transcription Factor 21; Ureteric bud branching.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / deficiency
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism
  • Down-Regulation
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Humans
  • Immunohistochemistry
  • Kidney / abnormalities
  • Kidney / embryology*
  • Kidney / metabolism*
  • Mesoderm / embryology
  • Mesoderm / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Morphogenesis / genetics
  • Pregnancy
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • GDNF protein, human
  • Gdnf protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • RNA, Messenger
  • TCF21 protein, human
  • Tcf21 protein, mouse
  • Wnt Proteins
  • Wnt11 protein, mouse
  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse