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

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Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development BASIC RESEARCH www.jasn.org Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development Shintaro Ide,1 Gal Finer,2,3 Yoshiro Maezawa,1 Tuncer Onay,3,4 Tomokazu Souma,3,4 Rizaldy Scott,3,4 Kana Ide,1 Yoshihiro Akimoto,5 Chengjin Li,6 Minghao Ye,3,4 Xiangmin Zhao,2,3 Yusuke Baba,1 Takuya Minamizuka,1 Jing Jin,3,4 Minoru Takemoto,1,7 Koutaro Yokote,1 and Susan E. Quaggin3,4 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background The mammalian kidney develops through reciprocal inductive signals between the meta- nephric mesenchyme and ureteric bud. Transcription factor 21 (Tcf21) is highly expressed in the meta- nephric 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,micewithstromal 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 down- regulated 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 mes- enchyme compartments during kidney development and suggest that Tcf21 regulates key molecular pathways required for branching morphogenesis. J Am Soc Nephrol 29: ccc–ccc, 2018. doi: https://doi.org/10.1681/ASN.2017121278 Received December 12, 2017. Accepted September 27, 2018. Development of the mouse metanephros begins at S.I. and G.F. contributed equally to this work. approximately embryonic day (E) 10.5 with induc- Published online ahead of print. Publication date available at tion of the ureteric bud (UB) at the posterior end of www.jasn.org. the nephric duct (also known as the Wolffian duct) by signals from the adjacent metanephric mesen- Correspondence: Dr. Yoshiro Maezawa, Clinical Cell Biology and Medicine and Department of Diabetes, Metabolism and 1,2 chyme (MM). TheUBinvadestheMM,elon- Endocrinology, Chiba University Graduate School of Medicine, 1- gates, and branches to form the renal collecting 8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan, or Dr. Susan E. system. As each branch forms, a subset of mesen- Quaggin, Division of Nephrology/Hypertension, Feinberg Car- diovascular and Renal Research Institute, Northwestern Univer- chymal cells aggregate and condense around the UB sity Feinberg School of Medicine, Suite 10-105, 303 E. Superior tips to form the Six2-expressing cap mesenchyme Street, Chicago, IL 60611. E-mail: [email protected] or (CM). This structure further differentiates into pre- [email protected] tubular aggregates, comma- and S-shaped bodies, Copyright © 2018 by the American Society of Nephrology J Am Soc Nephrol 29: ccc–ccc, 2018 ISSN : 1046-6673/2912-ccc 1 BASIC RESEARCH www.jasn.org and subsequently into the Bowman’s capsule of the glomeru- Significance Statement lus, podocytes, and the nephron down to the distal tubule.3–5 The Six2-positive CM is surrounded by Foxd1-expressing Branching morphogenesis of the ureteric bud is central to forming a stromal cells that are also derived from the MM and give normal kidney, and the most severe forms of congenital anomalies of rise to interstitial cells, mesangial cells, and pericytes.6 Disrup- the kidney and urinary tract (CAKUT) arise from mutations in genes involved in branching. The authors report that deletion in mice of tion of any of these events results in congenital anomalies of transcription factor 21 (Tcf21) results in a spectrum of renal de- the kidney and the lower urinary tract (CAKUT); these rep- velopmental phenotypes that resemble human CAKUT. Germline resent 20%–30% of all anomalies identified in the prenatal deletion of Tcf21 or Tcf21 deleted specifically from the stromal period in humans.7–10 mesenchyme resulted in branching defects and reduced expression Gdnf-Ret-Wnt11 Cell type–specific basic helix-loop-helix transcription of (a key pathway required for branching mor- phogenesis), whereas Tcf21 deletion specifically from the cap 11–14 factors are key regulators of organ morphogenesis. mesenchyme resulted in glomerular rather than branching defects Transcription factor 21 (Tcf21) (Pod1/Capsulin/Epicardin) and no downregulation of Gdnf-Ret-Wnt11. These findings suggest is a class 2 basic helix-loop-helix transcription factor that that Tcf21 has a central role in regulating the Gdnf axis and renal showsrobustexpressioninmesenchymalcellsoftheuro- stromal factors crucial for branching. genital, respiratory, digestive, and cardiovascular systems – throughout embryogenesis and is involved in epithelial were kind gifts from Dr. Andy McMahon (University of mesenchymal interactions in the kidney, lung, and other Southern California), and are described elsewhere.5,26 15–18 organs. In disease, Tcf21 is reported to function as a Rosa26-mT/mG reporter mice (JAX stock no. 007676) were tumor suppressor and loss of Tcf21 expression and/or meth- obtained from The Jackson Laboratory. ylation of its promoter have been identified in a variety of lung and urogenital tumors.19,20 In other studies, Tcf21 has been linked to coronary artery disease,21,22 podocyte differ- Immunostaining entiation, diabetic kidney disease,23 and changes in adipose For immunohistochemistry and lectin stainings, kidneys were fi phenotype.24 dissected and xed by 10% formalin or 4% paraformaldehyde fi In the kidney, previous work has shown that Tcf21 null overnight. Tissues were then embedded in paraf n and sliced m mutant mice are born with severely hypoplastic kidneys, and into 5- m-thick sections. Before immunostainings, sections fi that although Tcf21 is exclusively expressed in the mesen- were deparaf nized in xylene and ethanol and boiled in cit- fl chyme, in its absence, major defects in UB epithelial differen- rate buffer for antigen retrieval. For immuno uorescence, af- fi tiation and branching are observed.15,25 Currently, it remains ter xing by 4% paraformaldehyde overnight, tissues were unclear what signaling pathways are controlled by Tcf21. cryoprotected in 30% sucrose overnight and embedded in In this study, we report that Tcf21 regulates branching mor- Tissue-Tek O.C.T 4583 compound (Sakura Finetek Japan 2 m phogenesis by modifying the Gdnf-Ret-Wnt11 axis and pro- Co., Ltd., Tokyo, Japan) at 80°C and sliced into 10- m-thick vide data to support its pleiotropic functional roles that affect sections. UB-MM-stromal crosstalk. Using the Cre-LoxP system we These sections were blocked (0.3% Triton X-100, 3% show that Tcf21 has distinct roles in Foxd1-positive stromal albumin, 1 mM MgCl2, 1 mM CaCl2 in PBS) for 1 hour, cells and Six2-positive CM cells; where selective deletion of incubated with primary antibodies at 4°C overnight. After Tcf21 from the stromal cells results in branching defects, a washing several times by PBS, they were incubated with paucity of collecting ducts, and urine concentrating defects. secondary antibodies for 1 hour at room temperature. fl On the other hand, Tcf21 deletion in the CM leads to defects in Fluorescence-labeled Dolichos bi orus agglutinin (DBA) glomerulogenesis and massive proteinuria. or Lotus tetragonolobus lectin (LTL) was mixed with sec- ondary antibodies. For detailed methods and a full list of antibodies, see Supplemental Material and Supplemental METHODS Table 1. Ethics Statement/Study Approval Real-Time PCR All mouse experiments were performed in accordance with Whole kidneys were dissected and preserved at 280°C after institutional guidelines for animal studies. All animal experi- freezing in liquid nitrogen. They were treated by the ho- ments were approved by the Animal Care Committee at the mogenizer and QIA shredder (79656; Qiagen) and total Center for Comparative Medicine of Northwestern University RNA was extracted by using Pure link RNA minikit (Evanston, IL) or by the Chiba University Ethics Committee (12183025; Life Technologies). Reverse transcription was (Chiba, Japan). performed using Super Script III Reverse transcription (18080044; Invitrogen) according to the manuals. Quanti- Mice and Genotyping tative real-time PCR was performed using Fast SYBR Green Tcf21 lox/lox and Tcf21-LacZ mice were created as previously Master Mix (Thermo Fisher Scientific). Data were analyzed described.23,25 The Six2-eGFPCre and FoxD1-eGFPCre mice as the ratio to GAPDH. 2 Journal of the American Society of Nephrology J Am Soc Nephrol 29: ccc–ccc,2018 www.jasn.org BASIC RESEARCH A Control Tcf21 null E Control Tcf21 null Jagged1 / (E14.5) Ret Calbindin B 60 60 40 40 (E14.5) ** 20 *** 20 UB tips number number Wnt11 0 Jagged1(+) spot 0 Tcf21 Tcf21 Control null Control null F Control Tcf21 null C Gdnf Ret Wnt11 1.5 1.5 2.0 1.5 1.0 1.0 1.0 Gdnf (E14.5) ** 0.5 ** 0.5 0.5 Fold change *** 0.0 0.0 0.0 Tcf21 Tcf21 Tcf21 Control null Control null Control null D Control Tcf21 null E-cadherin (E14.5) (E12.5) Gdnf Gdnf (E16.5) (E14.5) Gdnf E-cadherin (E16.5) Figure 1. UB branching is impaired and Gdnf, Ret, and Wnt11 are downregulated in Tcf21 null kidneys.
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