Transcription factor 21 is required for branching morphogenesis and regulates the Gdnf-Axis in kidney development

Shintaro Ide, Gal Finer, Yoshiro Maezawa*, Tuncer Onay, Tomokazu Souma, Rizaldy P Scott, Kana Ide, Yoshihiro Akimoto, Chengjin Li, Minghao Ye, Xiangmin Zhao, Yusuke Baba, Takuya Minamizuka, Jing Jin, Minoru Takemoto, Koutaro Yokote, Susan E Quaggin

*Corresponding author for this work

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2795-2808
Number of pages14
JournalJournal of the American Society of Nephrology
Volume29
Issue number12
DOIs
StatePublished - Dec 1 2018

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Morphogenesis
Transcription Factors
Mesoderm
Kidney
Down-Regulation
Proteinuria
Knockout Mice
Fetus
Urine
Phenotype
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Nephrology

Cite this

Ide, Shintaro ; Finer, Gal ; Maezawa, Yoshiro ; Onay, Tuncer ; Souma, Tomokazu ; Scott, Rizaldy P ; Ide, Kana ; Akimoto, Yoshihiro ; Li, Chengjin ; Ye, Minghao ; Zhao, Xiangmin ; Baba, Yusuke ; Minamizuka, Takuya ; Jin, Jing ; Takemoto, Minoru ; Yokote, Koutaro ; Quaggin, Susan E. / Transcription factor 21 is required for branching morphogenesis and regulates the Gdnf-Axis in kidney development. In: Journal of the American Society of Nephrology. 2018 ; Vol. 29, No. 12. pp. 2795-2808.
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title = "Transcription factor 21 is required for branching morphogenesis and regulates the Gdnf-Axis in kidney development",
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.",
author = "Shintaro Ide and Gal Finer and Yoshiro Maezawa and Tuncer Onay and Tomokazu Souma and Scott, {Rizaldy P} and Kana Ide and Yoshihiro Akimoto and Chengjin Li and Minghao Ye and Xiangmin Zhao and Yusuke Baba and Takuya Minamizuka and Jing Jin and Minoru Takemoto and Koutaro Yokote and Quaggin, {Susan E}",
year = "2018",
month = "12",
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doi = "10.1681/ASN.2017121278",
language = "English (US)",
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Ide, S, Finer, G, Maezawa, Y, Onay, T, Souma, T, Scott, RP, Ide, K, Akimoto, Y, Li, C, Ye, M, Zhao, X, Baba, Y, Minamizuka, T, Jin, J, Takemoto, M, Yokote, K & Quaggin, SE 2018, 'Transcription factor 21 is required for branching morphogenesis and regulates the Gdnf-Axis in kidney development', Journal of the American Society of Nephrology, vol. 29, no. 12, pp. 2795-2808. https://doi.org/10.1681/ASN.2017121278

Transcription factor 21 is required for branching morphogenesis and regulates the Gdnf-Axis in kidney development. / Ide, Shintaro; Finer, Gal; Maezawa, Yoshiro; Onay, Tuncer; Souma, Tomokazu; Scott, Rizaldy P; Ide, Kana; Akimoto, Yoshihiro; Li, Chengjin; Ye, Minghao; Zhao, Xiangmin; Baba, Yusuke; Minamizuka, Takuya; Jin, Jing; Takemoto, Minoru; Yokote, Koutaro; Quaggin, Susan E.

In: Journal of the American Society of Nephrology, Vol. 29, No. 12, 01.12.2018, p. 2795-2808.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Transcription factor 21 is required for branching morphogenesis and regulates the Gdnf-Axis in kidney development

AU - Ide, Shintaro

AU - Finer, Gal

AU - Maezawa, Yoshiro

AU - Onay, Tuncer

AU - Souma, Tomokazu

AU - Scott, Rizaldy P

AU - Ide, Kana

AU - Akimoto, Yoshihiro

AU - Li, Chengjin

AU - Ye, Minghao

AU - Zhao, Xiangmin

AU - Baba, Yusuke

AU - Minamizuka, Takuya

AU - Jin, Jing

AU - Takemoto, Minoru

AU - Yokote, Koutaro

AU - Quaggin, Susan E

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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U2 - 10.1681/ASN.2017121278

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JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

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