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Loss of the Podocyte-Expressed Transcription Factor Tcf21/Pod1 Results in Podocyte Differentiation Defects and FSGS

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Loss of the Podocyte-Expressed Transcription Factor Tcf21/Pod1 Results in Podocyte Differentiation Defects and FSGS BASIC RESEARCH www.jasn.org Loss of the Podocyte-Expressed Transcription Factor Tcf21/Pod1 Results in Podocyte Differentiation Defects and FSGS † ‡ Yoshiro Maezawa,* Tuncer Onay,* Rizaldy P. Scott,* Lindsay S. Keir,§ Henrik Dimke,* ‡ | Chengjin Li,* Vera Eremina,* Yuko Maezawa, Marie Jeansson,*¶ Jingdong Shan,** †† ‡‡ ‡ Matthew Binnie, Moshe Lewin, Asish Ghosh, Jeffrey H. Miner,§§ Seppo J. Vainio,** ‡ and Susan E. Quaggin* *The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; †Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan; ‡Feinberg Cardiovascular Research Institute and Division of Nephrology and Hypertension, Northwestern University, Chicago, Illinois; §Academic Renal Unit, University of Bristol, Bristol, United Kingdom; |Neuroscience and Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; ¶Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; **Biocenter and Infotech Oulu, Laboratory of Developmental Biology, Faculty of Biochemisty and Molecular Medicine, Oulu Center for Cell Matrix Research, University of Oulu, Finland; ††Division of Respirology, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; ‡‡Department of Nephrology, RAMBAM Health Care Campus, Haifa, Israel; and §§Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri ABSTRACT Podocytes are terminally differentiated cells with an elaborate cytoskeleton and are critical components of the glomerular barrier. We identified a bHLH transcription factor, Tcf21, that is highly expressed in developing and mature podocytes. Because conventional Tcf21 knockout mice die in the perinatal period with major cardiopulmonary defects, we generated a conditional Tcf21 knockout mouse to explore the role of this transcription factor in podocytes in vivo. Tcf21 was deleted from podocytes and podocyte progenitors using podocin-cre (podTcf21) and wnt4-cre (wnt4creTcf21) driver strains, respectively. Loss of Tcf21 from capillary-loop stage podocytes (podTcf21) results in simplified glomeruli with a decreased number of endothelial and mesangial cells. By 5 weeks of age, 40% of podTcf21 mice develop massive proteinuria and lesions similar to FSGS. Notably, the remaining 60% of mice do not develop proteinuria even when aged to 8 months. By contrast, earlier deletion of Tcf21 from podocyte precursors (wnt4creTcf21) results in a profound developmental arrest of podocyte differentiation and renal failure in 100% of mice during the perinatal period. Taken together, our results demonstrate a critical role for Tcf21 in the differentiation and maintenance of podocytes. Identification of direct targets of this tran- scription factor may provide new therapeutic avenues for proteinuric renal disease, including FSGS. J Am Soc Nephrol 25: 2459–2470, 2014. doi: 10.1681/ASN.2013121307 Over the past decade, many landmark studies have of these genes can cause neonatal and adult human demonstrated a central role for podocytes in renal nephrotic syndromes.1 Furthermore, podocytes health and disease. Mature podocytes extend elab- orate foot processes that interdigitate with each Received December 16, 2013. Accepted February 8, 2014. other and are connected by a specialized intercel- Published online ahead of print. Publication date available at lular junction called the slit diaphragm. The slit www.jasn.org. diaphragm is composed of several proteins, in- Correspondence: Dr. Susan E. Quaggin, Lurie Medical Research cluding nephrin, podocin, and Cd2-associated pro- Building, 303 E Superior, Chicago, IL 60611. Email: quaggin@ tein, that interact with actin-based cytoskeletal northwestern.edu proteins, such as a-actinin 4. Mutations in each Copyright © 2014 by the American Society of Nephrology J Am Soc Nephrol 25: 2459–2470, 2014 ISSN : 1046-6673/2511-2459 2459 BASIC RESEARCH www.jasn.org communicate with other cell types in the glomerulus, and are RESULTS able to monitor their extracellular environment and modify their shape and function accordingly.2 As a result, dysregula- Generation of a Floxed Tcf21 Founder Mouse Line tion in a number of signaling pathways and factors produced The Tcf21 conditional allele was designed with LoxP sites by podocytes, such as vascular endothelial growth factor inserted around the first exon, which contains the bHLH (VEGF), can also cause glomerular injury.3,4 domain (Figure 1A). After electroporation, embryonic stem During development, podocyte precursors appear at the (ES) cell clones were screened by Southern blot analysis with end of the S-shaped body farthest from the ureteric bud and probes outside the homology regions. One positive clone (5G differentiate through a well defined sequence of morphologic clone in Figure 1B) was used to generate chimeric mice. events from a columnar-shaped epithelium facing the vascular To confirm that the Cre-mediated gene deletion results in a cleft to mature podocytes with their elaborate foot processes. null Tcf21 allele, we generated inducible whole-body Tcf21 Several transcription factors have been identified that are knockout mice using the ROSA-rtTA/tetO-Cre system. Ad- expressed by podocyte precursors, including Wilms’ tumor ministration of doxycycline to the dam from the time of con- suppressor 1 (Wt1), Lmx1b, Foxc2, and MafB. Wt1 is a zinc ceptionresultedinmutantembryosthatshowpericardial finger–containing transcription factor, and genetic deletion bleeding and severely hypoplastic lungs and kidneys at embry- of Wt1 leads to loss of nephrogenic induction and renal onic day 18.5, which are identical to the defects caused by agenesis.5 Glomeruli in knockout mice for Lmx1b or Foxc2 phenotype observed in conventional Tcf21 knockout mice are abnormal, with arrested podocyte differentiation, sim- (Figure 1C). This finding confirmed that the deleted condi- plified capillary loop structure, and defects in mesangial cell tional allele is indeed a null allele. Subsequent genotyping was ingrowth.6,7 Global deletion of MafB also results in abnor- performed by PCR (Figure 1D). mal foot process formation, with persistence of “flat feet” in podocytes.8 Normal Differentiation of Podocytes and Delay of Tcf21 (Pod1/capsulin/epicardin) is a basic helix-loop-helix Glomerular Maturation in Podocyte-Specific Tcf21 (bHLH) transcription factor whose expression is highest in Knockout Mice podocyte precursors and is maintained in mature podocytes. Previously we showed that conventional Tcf21 knockout mice However, at earlier stages of metanephric development, Tcf21 demonstrate an arrest of glomerular maturation (Figure 2A).9 is expressed in both Six2-expressing nephron progenitors and To examine the role of Tcf21 exclusively in podocytes, floxed Foxd1-expressing stromal mesenchyme.9–11 Global deletion Tcf21 mice were bred to transgenic podocin-cre mice to create studies of Tcf21 have shown that it is required for the devel- podocyte-specific knockout (podTcf21) mice. Using a Z/EG opment of lung, heart, kidney, gonad, spleen, and facial mus- reporter mouse,15 we confirmed that podocin-cre results in cles.9,12–14 The kidneys of Tcf21 knockout mice are severely gene excision from the capillary loop stage onward and not at hypoplastic because of a delay of nephrogenesis and abnormal the S-shape stage (Supplemental Figure 1A). At postnatal day branching morphogenesis of the ureteric bud.9 The few glo- 0, although Tcf21 expression was properly decreased in meruli found in kidneys of Tcf21 knockout mice appear to podocytes, podTcf21 glomeruli showed almost normal histo- arrest at the capillary loop stage of development. However, logic features and ultrastructure (Figure 2B). Mice were born because Tcf21 is also involved in the induction of nephrogen- in the expected Mendelian ratio, and podTcf21 pups appeared esis from the Six2-positive progenitor population, it has not healthy for 2 weeks (data not shown). These results indicate been possible to determine the roles of Tcf21 in developing that Tcf21 is not required for terminal differentiation of and mature podocytes. Indeed, the glomerular defects might podocytes after the capillary loop stage. reflect roles of Tcf21 in the progenitor or adjacent cell popu- However, immunostainings for podocin and endothelial lations, rather than in the podocyte itself. markers(Cd31andendomucin)revealedasurprisingly Here we report the phenotype in mice following podocyte- simplified glomerular structure at postnatal day 0 and 3 weeks selective knockout of Tcf21. Deletion of Tcf21 in relatively of age (Figure 2C). Immunostaining for a mesangial marker, mature podocytes (podocin-cre) allows podocyte differenti- desmin, showed a similar finding (Supplemental Figure 1B). ation to occur but results in a simplified glomerular structure. Interestingly, at P0, although the Wt1-positive podocyte num- However, 40% of podocyte-specific Tcf21 knockout mice ber did not differ, total cell number and nonpodocyte cell develop massive proteinuria at 3–5 weeks of age with prom- number in mutant glomeruli were reduced by 15% and inent glomerular lesions similar to human FSGS. By contrast, 25%, respectively (Figure 2D). Taken together, these findings earlier deletion of Tcf21 at the renal vesicle stage of glomerular suggest a delay in glomerular maturation with reduced influx development using a wnt4-cre driver line results in major de- and/or in situ proliferation of endothelial and mesangial cells. fects in podocyte differentiation.
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