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      The Regulation of Apoptosis in Kidney Development: Implications for Nephron Number and Pattern?

      review-article
      1 , *
      Frontiers in Pediatrics
      Frontiers Media S.A.
      kidney development, apoptosis, nephron number, nephron pattern, cystic kidney disease

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          Abstract

          Apoptosis is essential to remodel developing structures and eliminate superfluous cells in a controlled manner during normal development, and continues to be an important component of tissue remodeling and regeneration during an organism’s lifespan, or as a response to injury. This mini review will discuss recent studies that have provided insights into the roles of apoptosis in the determination of nephron number and pattern, during normal and abnormal kidney development. The regulation of congenital nephron endowment has implications for risk of chronic kidney disease in later life, whereas abnormalities in nephron pattern are associated with congenital anomalies of the kidney and urinary tract (the leading cause of renal disease in children). Tight regulation of apoptosis is required in normal renal morphogenesis, although many questions remain regarding the regulation of apoptosis by genetic, epigenetic, and environmental factors, in addition to the functional requirement of different components of the apoptotic pathway.

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          Most cited references50

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          Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.

          Apoptosis can be triggered by members of the Bcl-2 protein family, such as Bim, that share only the BH3 domain with this family. Gene targeting in mice revealed important physiological roles for Bim. Lymphoid and myeloid cells accumulated, T cell development was perturbed, and most older mice accumulated plasma cells and succumbed to autoimmune kidney disease. Lymphocytes were refractory to apoptotic stimuli such as cytokine deprivation, calcium ion flux, and microtubule perturbation but not to others. Thus, Bim is required for hematopoietic homeostasis and as a barrier to autoimmunity. Moreover, particular death stimuli appear to activate apoptosis through distinct BH3-only proteins.
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            Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development.

            Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to nephrons and how multiple nephron lineages form during this protracted developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent nephron progenitor population.
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              WT-1 is required for early kidney development.

              In humans, germline mutations of the WT-1 tumor suppressor gene are associated with both Wilms' tumors and urogenital malformations. To develop a model system for the molecular analysis of urogenital development, we introduced a mutation into the murine WT-1 tumor suppressor gene by gene targeting in embryonic stem cells. The mutation resulted in embryonic lethality in homozygotes, and examination of mutant embryos revealed a failure of kidney and gonad development. Specifically, at day 11 of gestation, the cells of the metanephric blastema underwent apoptosis, the ureteric bud failed to grow out from the Wolffian duct, and the inductive events that lead to formation of the metanephric kidney did not occur. In addition, the mutation caused abnormal development of the mesothelium, heart, and lungs. Our results establish a crucial role for WT-1 in early urogenital development.
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                Author and article information

                Contributors
                Journal
                Front Pediatr
                Front Pediatr
                Front. Pediatr.
                Frontiers in Pediatrics
                Frontiers Media S.A.
                2296-2360
                30 October 2014
                18 November 2014
                2014
                : 2
                : 128
                Affiliations
                [1] 1Department of Pediatrics, Division of Nephrology, University of Pittsburgh School of Medicine , Pittsburgh, PA, USA
                Author notes

                Edited by: Peter Trnka, University of Queensland, Australia

                Reviewed by: Denise K. Marciano, University of Texas Southwestern Medical Center, USA; Andrew Mallett, Royal Brisbane and Women’s Hospital, Australia

                *Correspondence: Jacqueline Ho, Department of Pediatrics, Division of Nephrology, Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, 4401 Penn Ave, Pittsburgh, PA 15224, USA e-mail: jacqueline.ho2@ 123456chp.edu

                This article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics.

                Article
                10.3389/fped.2014.00128
                4235295
                25478553
                ff083c06-2a99-4a2d-8b82-4dd0b15714ed
                Copyright © 2014 Ho.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 October 2014
                : 05 November 2014
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 58, Pages: 6, Words: 4764
                Categories
                Pediatrics
                Mini Review

                kidney development,apoptosis,nephron number,nephron pattern,cystic kidney disease

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