Melissa H Little

University of Melbourne, Melbourne, Victoria, Australia

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Publications (155)863.66 Total impact

  • J M Vanslambrouck · M H Little
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    ABSTRACT: The direct reprogramming of one cell fate to another represents an attractive option for the generation of specific endpoints for cellular therapy. This appears to require both the reactivation of critical transcription factor regulatory networks and chromatin remodelling. The direct reprogramming of mature renal epithelial cell lines to a nephron progenitor state has been reported. However, our limited knowledge of the optimal growth conditions to maintain this state remains a challenge for their therapeutic application. Here we examine whether nephron progenitors as an endpoint of direct reprogramming have been suitably defined and whether alternative options for reprogramming to kidney exist. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Current opinion in genetics & development 07/2015; 34:10-16. DOI:10.1016/j.gde.2015.06.001 · 7.57 Impact Factor
  • Melissa H Little
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    ABSTRACT: As with many mammalian organs, size and cellular complexity represent considerable challenges to the comprehensive analysis of kidney organogenesis. Traditional analyses in the mouse have revealed early patterning events and spatial cellular relationships. However, an understanding of later events is lacking. The generation of a comprehensive temporospatial atlas of gene expression during kidney development has facilitated advances in lineage definition, as well as selective compartment ablation. Advances in quantitative and dynamic imaging have allowed comprehensive analyses at the level of organ, component tissue and cell across kidney organogenesis. Such approaches will enhance our understanding of the links between kidney development and final postnatal organ function. The final frontier will be translating this understanding to outcomes for renal disease in humans. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Current opinion in genetics & development 06/2015; 32. DOI:10.1016/j.gde.2015.03.001 · 7.57 Impact Factor
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    ABSTRACT: ROBO2 plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations in humans and mice leading to supernumerary kidneys. Previous studies have established that the number and position of UB outgrowths is determined by the domain of metanephric mesenchymal Gdnf expression, which is expanded anteriorly in Robo2 mouse mutants. To clarify how this phenotype arises, we used high-resolution 3D imaging to reveal an increase in the number of nephrogenic cord cells, leading to extension of the metanephric mesenchyme field in Robo2-null mouse embryos. Ex vivo experiments suggested a dependence of this effect on proliferative signals from the Wolffian duct. Loss of Robo2 resulted in a failure of the normal separation of the mesenchyme from the Wolffian duct/ureteric epithelium, suggesting that aberrant juxtaposition of these two compartments in Robo2-null mice exposes the mesenchyme to abnormally high levels of proliferative stimuli. Our data suggest a new model in which SLIT-ROBO signalling acts not by attenuating Gdnf expression or activity, but instead by limiting epithelial/mesenchymal interactions in the nascent metanephros and restricting the extent of the nephrogenic field. These insights illuminate the etiology of multiplex kidney formation in human individuals with ROBO2 mutations. Copyright © 2015. Published by Elsevier Inc.
    Developmental Biology 06/2015; 404(2). DOI:10.1016/j.ydbio.2015.05.023 · 3.55 Impact Factor
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    Minoru Takasato · Melissa H Little
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    ABSTRACT: The mammalian kidney, the metanephros, is a mesodermal organ classically regarded as arising from the intermediate mesoderm (IM). Indeed, both the ureteric bud (UB), which gives rise to the ureter and the collecting ducts, and the metanephric mesenchyme (MM), which forms the rest of the kidney, derive from the IM. Based on an understanding of the signalling molecules crucial for IM patterning and kidney morphogenesis, several studies have now generated UB or MM, or both, in vitro via the directed differentiation of human pluripotent stem cells. Although these results support the IM origin of the UB and the MM, they challenge the simplistic view of a common progenitor for these two populations, prompting a reanalysis of early patterning events within the IM. Here, we review our understanding of the origin of the UB and the MM in mouse, and discuss how this impacts on kidney regeneration strategies and furthers our understanding of human development. © 2015. Published by The Company of Biologists Ltd.
    Development 06/2015; 142(11):1937-1947. DOI:10.1242/dev.104802 · 6.46 Impact Factor
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    ABSTRACT: There has been intensive effort to identify in vivo biomarkers that can be used to monitor drug-induced kidney damage and identify injury before significant impairment occurs. Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and human macrophage colony stimulating factor (M-CSF) have been validated as urinary and plasma clinical biomarkers predictive of acute and chronic kidney injury and disease. Similar validation of a high throughput in vitro assay predictive of nephrotoxicity could potentially be implemented early in drug discovery lead optimization to reduce attrition at later stages of drug development. To assess these known in vivo biomarkers for their potential for in vitro screening of drug-induced nephrotoxicity, we selected a panel of nephrotoxic agents and examined their effects on the overexpression of nephrotoxicity biomarkers in immortalized (HK-2) and primary (commercially available and freshly in-house produced) human renal proximal tubule epithelial cells. Traditional cytotoxicity was contrasted with expression levels of KIM-1, NGAL, and M-CSF assessed using ELISA and real-time quantitative reverse transcription PCR. Traditional cytotoxicity assays and biomarker assays using HK-2 cells were both unsuitable for prediction of nephrotoxicity. However, increases in protein levels of KIM-1 and NGAL in primary cells were well correlated with dose levels of known nephrotoxic compounds, with limited correlation seen in M-CSF protein and mRNA levels. These results suggest that profiling compounds against primary cells with monitoring of biomarker protein levels may have potential as in vitro predictive assays of drug-induced nephrotoxicity.
    06/2015; 3(3). DOI:10.1002/prp2.148
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    ABSTRACT: Malformation of the urogenital tract represents a considerable paediatric burden, with many defects affecting the lower urinary tract (LUT), genital tubercle and associated structures. Understanding the molecular basis of such defects frequently draws on murine models. However, human anatomical terms do not always superimpose on the mouse, and the lack of accurate and standardised nomenclature is hampering the utility of such animal models. We previously developed an anatomical ontology for the murine urogenital system. Here, we present a comprehensive update of this ontology pertaining to mouse LUT, genital tubercle and associated reproductive structures (E10.5 to adult). Ontology changes were based on recently published insights into the cellular and gross anatomy of these structures, and on new analyses of epithelial cell types present in the pelvic urethra and regions of the bladder. Ontology changes include new structures, tissue layers and cell types within the LUT, external genitalia and lower reproductive structures. Representative illustrations, detailed text descriptions and molecular markers that selectively label muscle, nerves/ganglia and epithelia of the lower urogenital system are also presented. The revised ontology will be an important tool for researchers studying urogenital development/malformation in mouse models and will improve our capacity to appropriately interpret these with respect to the human situation. © 2015. Published by The Company of Biologists Ltd.
    Development 05/2015; 142(10):1893-908. DOI:10.1242/dev.117903 · 6.46 Impact Factor
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    ABSTRACT: Kidney development is initiated by the outgrowth of an epithelial ureteric bud into a population of mesenchymal cells. Reciprocal morphogenetic responses between these two populations generate a highly branched epithelial ureteric tree with the mesenchyme differentiating into nephrons, the functional units of the kidney. While we understand some of the mechanisms involved, current knowledge fails to explain the variability of organ sizes and nephron endowment in mice and humans. Here we present a spatially-averaged mathematical model of kidney morphogenesis in which the growth of the two key populations is described by a system of time-dependant ordinary differential equations. We assume that branching is symmetric and is invoked when the number of epithelial cells per tip reaches a threshold value. This process continues until the number of mesenchymal cells falls below a critical value that triggers cessation of branching. The mathematical model and its predictions are validated against experimentally quantified C57Bl6 mouse embryonic kidneys. Numerical simulations are performed to determine how the final number of branches changes as key system parameters are varied (such as the growth rate of tip cells, mesenchyme cells, or component cell population exit rate). Our results predict that the developing kidney responds differently to loss of cap and tip cells. They also indicate that the final number of kidney branches is less sensitive to changes in the growth rate of the ureteric tip cells than to changes in the growth rate of the mesenchymal cells. By inference, increasing the growth rate of mesenchymal cells should maximise branch number. Our model also provides a framework for predicting the branching outcome when ureteric tip or mesenchyme cells change behaviour in response to different genetic or environmental developmental stresses. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Theoretical Biology 04/2015; 379. DOI:10.1016/j.jtbi.2015.04.015 · 2.12 Impact Factor
  • Melissa H. Little · Minoru Takasato
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    ABSTRACT: Recent studies on the directed differentiation of human pluripotent stem cells report tissue self-organization in vitro such that multiple component cell types arise in concert and arrange with respect to each, thereby recapitulating the morphogenetic events typical for that organ. Such self-organization has generated pituitary, optic cup, liver, brain, intestine, stomach and now kidney. Here, we will describe the cell types present within the self-organizing kidney, how these signal to each other to form a kidney organoid and the potential applications of kidney organoids. Protocols for the directed differentiation of human pluripotent cells focus on recapitulating the developmental steps required during embryogenesis. In the case of the kidney, this has involved mesodermal differentiation through posterior primitive streak and intermediate mesoderm. Recent studies have observed the simultaneous formation of both ureteric epithelium and nephron progenitors in vitro. These component cell types signal to each other to initiate nephron formation as would occur during development. The generation of kidney organoids is a major advance in nephrology. Such organoids may be useful for disease modelling and drug screening. Ultimately, our capacity to generate organoids may extend to the development of tissues for transplantation.
    Current Opinion in Organ Transplantation 04/2015; 20(2). DOI:10.1097/MOT.0000000000000174 · 2.88 Impact Factor
  • Alexander N Combes · Jamie A Davies · Melissa H Little
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    ABSTRACT: The mammalian kidney forms via cell-cell interactions between an epithelial outgrowth of the nephric duct and the surrounding nephrogenic mesenchyme. Initial morphogenetic events include ureteric bud branching to form the collecting duct (CD) tree and mesenchymal-to-epithelial transitions to form the nephrons, requiring reciprocal induction between adjacent mesenchyme and epithelial cells. Within the tips of the branching ureteric epithelium, cells respond to mesenchyme-derived trophic factors by proliferation, migration, and mitosis-associated cell dispersal. Self-inhibition signals from one tip to another play a role in branch patterning. The position, survival, and fate of the nephrogenic mesenchyme are regulated by ECM and secreted signals from adjacent tip and stroma. Signals from the ureteric tip promote mesenchyme self-renewal and trigger nephron formation. Subsequent fusion to the CDs, nephron segmentation and maturation, and formation of a patent glomerular basement membrane also require specialized cell-cell interactions. Differential cadherin, laminin, nectin, and integrin expression, as well as intracellular kinesin and actin-mediated regulation of cell shape and adhesion, underlies these cell-cell interactions. Indeed, the capacity for the kidney to form via self-organization has now been established both via the recapitulation of expected morphogenetic interactions after complete dissociation and reassociation of cellular components during development as well as the in vitro formation of 3D kidney organoids from human pluripotent stem cells. As we understand more about how the many cell-cell interactions required for kidney formation operate, this enables the prospect of bioengineering replacement structures based on these self-organizing properties. © 2015 Elsevier Inc. All rights reserved.
    Current Topics in Developmental Biology 03/2015; 112:467-508. DOI:10.1016/bs.ctdb.2014.12.002 · 4.68 Impact Factor
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    ABSTRACT: Gestational stressors, including glucocorticoids and protein restriction, can affect kidney development and hence final nephron number. Since hypoxia is a common insult during pregnancy, we studied the influence of oxygen tension on kidney development in models designed to represent a pathological hypoxic insult. In vivo mouse models of moderate, transient, midgestational (12% O2, 48 h, 12.5 dpc) or severe, acute, early-gestational (5.5-7.5% O2, 8 h, 9.5-10.5 dpc) hypoxia were developed. The embryo itself is known to mature under hypoxic conditions with embryonic tissue levels of oxygen estimated to be 5%-8% (physiological hypoxia) when the mother is exposed to ambient normoxia. Both in vivo models generated phenotypes seen in patients with congenital anomalies of the kidney and urinary tract (CAKUT). Severe, acute, early hypoxia resulted in duplex kidney, while moderate, transient, midgestational hypoxia permanently reduced ureteric branching and nephron formation. Both models displayed hypoxia-induced reductions in β-catenin signaling within the ureteric tree and suppression of the downstream target gene, Ccnd1. Thus, we show a link between gestational hypoxia and CAKUT, the phenotype of which varies with timing, duration, and severity of the hypoxic insult.Kidney International advance online publication, 14 January 2015; doi:10.1038/ki.2014.394.
    Kidney International 01/2015; 87(5). DOI:10.1038/ki.2014.394 · 8.56 Impact Factor
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    ABSTRACT: Developmental branching morphogenesis establishes organ architecture, and it is driven by iterative interactions between epithelial and mesenchymal progenitor cell populations. We describe an approach for analyzing this interaction and how it contributes to organ development. After initial in vivo cell labeling with the nucleoside analog 5-ethynyl-2'-deoxyuridine (EdU) and tissue-specific antibodies, optical projection tomography (OPT) and confocal microscopy are used to image the developing organ. These imaging data then inform a second analysis phase that quantifies (using Imaris and Tree Surveyor software), models and integrates these events at a cell and tissue level in 3D space and across developmental time. The protocol establishes a benchmark for assessing the impact of genetic change or fetal environment on organogenesis that does not rely on ex vivo organ culture or section-based reconstruction. By using this approach, examination of two developmental stages for an organ such as the kidney can be undertaken by a postdoctoral-level researcher in 6 weeks, with a full developmental analysis in mouse achievable in 5 months.
    Nature Protocols 12/2014; 9(12):2859-79. DOI:10.1038/nprot.2014.193 · 9.67 Impact Factor
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    ABSTRACT: The National Institute of Diabetes and Digestive and Kidney Diseases-supported Kidney Research National Dialogue asked the scientific community to formulate and prioritize research objectives that would improve our understanding of kidney function and disease; >1600 participants from >30 countries posted >300 ideas and >500 comments covering all areas of kidney research. Smaller groups of investigators interrogated the postings and published a series of commentaries in CJASN. Additional review of the entire series identified six cross-cutting themes: (1) increase training and team science opportunities to maintain/expand the nephrology workforce, (2) develop novel technologies to assess kidney function, (3) promote human discovery research to better understand normal and diseased kidney function, (4) establish integrative models of kidney function to inform diagnostic and treatment strategies, (5) promote interventional studies that incorporate more responsive outcomes and improved trial designs, and (6) foster translation from clinical investigation to community implementation. Together, these cross-cutting themes provide a research plan to better understand normal kidney biology and improve the prevention, diagnosis, and treatment of kidney disease, and as such, they will inform future research efforts supported by the National Institute of Diabetes and Digestive and Kidney Diseases through workshops and initiatives.
    Clinical Journal of the American Society of Nephrology 09/2014; 9(10). DOI:10.2215/CJN.07310714 · 4.61 Impact Factor
  • Minoru Takasato · Jessica M. Vanslambrouck · Melissa H. Little
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    ABSTRACT: Recent years have challenged the view that adult somatic cells reach a state of terminal differentiation. While the ultimate example of this, somatic cell nuclear transfer, has not proven feasible in humans, dedifferentiation of mature cell types to a more primitive state, direct reprogramming from one mature state to another and the reprogramming of any adult cell type to a pluripotent state via enforced expression of key transcription factors have all now been demonstrated. The implications of these findings for kidney disease include the recreation of key renal cell types from more readily available and expandable somatic cell sources. The feasibility of such an approach has been recently demonstrated with the dedifferentiation of proximal tubule cells to nephrogenic mesenchyme. In this review, we examine the technical challenges and clinical challenges that remain to such an approach and how new reprogramming approaches may also be useful for kidney disease.
    Seminars in Nephrology 07/2014; 34(4). DOI:10.1016/j.semnephrol.2014.06.012 · 3.48 Impact Factor
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    ABSTRACT: We previously described a mesenchymal stem cell (MSC)-like population within the adult mouse kidney that displays long-term colony-forming efficiency, clonogenicity, immunosuppression, and panmesodermal potential. Although phenotypically similar to bone marrow (BM)-MSCs, kidney MSC-like cells display a distinct expression profile. FACS sorting from Hoxb7/enhanced green fluorescent protein (GFP) mice identified the collecting duct as a source of kidney MSC-like cells, with these cells undergoing an epithelial-to-mesenchymal transition to form clonogenic, long-term, self-renewing MSC-like cells. Notably, after extensive passage, kidney MSC-like cells selectively integrated into the aquaporin 2-positive medullary collecting duct when microinjected into the kidneys of neonatal mice. No epithelial integration was observed after injection of BM-MSCs. Indeed, kidney MSC-like cells retained a capacity to form epithelial structures in vitro and in vivo, and conditioned media from these cells supported epithelial repair in vitro. To investigate the origin of kidney MSC-like cells, we further examined Hoxb7(+) fractions within the kidney across postnatal development, identifying a neonatal interstitial GFP(lo) (Hoxb7(lo)) population displaying an expression profile intermediate between epithelium and interstitium. Temporal analyses with Wnt4(GCE/+):R26(tdTomato/+) mice revealed evidence for the intercalation of a Wnt4-expressing interstitial population into the neonatal collecting duct, suggesting that such intercalation may represent a normal developmental mechanism giving rise to a distinct collecting duct subpopulation. These results extend previous observations of papillary stem cell activity and collecting duct plasticity and imply a role for such cells in collecting duct formation and, possibly, repair.
    Journal of the American Society of Nephrology 06/2014; 26(1). DOI:10.1681/ASN.2013050517 · 9.34 Impact Factor
  • 35th Annual Scientific Meeting of the; 06/2014
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    ABSTRACT: Maternal hypoxia is a common perturbation that can disrupt placental and thus fetal development, contributing to neonatal impairments. Recently, evidence has suggested that physiological outcomes are dependent upon the sex of the fetus with males more susceptible to hypoxic insults than females. This study investigated the effects of maternal hypoxia during mid-late gestation on fetal growth and placental development and determined if responses were sex specific. CD1 mice were housed under 21% or 12% oxygen from embryonic day (E) 14.5 until tissue collection at E18.5. Fetuses and placentas were weighed before collection for gene and protein expression and morphological analysis. Hypoxia reduced fetal weight in both sexes at E18.5 by 7% but did not affect placental weight. Hypoxia reduced placental mRNA levels of the mineralocorticoid and glucocorticoid receptors and reduced the gene and protein expression of the glucocorticoid metabolizing enzyme, HSD11B2. However, placentas of female fetuses responded differently to maternal hypoxia than did placentas of male fetuses. Notably, morphology was significantly altered in placentas from hypoxic female fetuses with a reduction in placental labyrinth blood spaces. In addition mRNA expression of Glut1, Igf2 and Igf1r were reduced in placentas of female fetuses only. In summary, maternal hypoxia altered placental formation in a sex specific manner through mechanisms involving placental vascular development, growth factor and nutrient transporter expression and placental glucocorticoid signalling. This study provides insight into how sex differences in offspring disease development may be due to sex specific placental adaptations to maternal insults.This article is protected by copyright. All rights reserved
    The Journal of Physiology 05/2014; 6(14). DOI:10.1113/jphysiol.2014.272856 · 5.04 Impact Factor
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    ABSTRACT: Although kidneys of equal size can vary 10-fold in nephron number at birth, discovering what regulates such variation has been hampered by a lack of quantitative parameters defining kidney development. Here we report a comprehensive, quantitative, multiscale analysis of mammalian kidney development in which we measure changes in cell number, compartment volumes, and cellular dynamics across the entirety of organogenesis, focusing on two key nephrogenic progenitor populations: the ureteric epithelium and the cap mesenchyme. In doing so, we describe a discontinuous developmental program governed by dynamic changes in interactions between these key cellular populations occurring within a previously unappreciated structurally stereotypic organ architecture. We also illustrate the application of this approach to the detection of a subtle mutant phenotype. This baseline program of kidney morphogenesis provides a framework for assessing genetic and environmental developmental perturbation and will serve as a gold standard for the analysis of other organs.
    Developmental Cell 04/2014; 29(2):188-202. DOI:10.1016/j.devcel.2014.02.017 · 9.71 Impact Factor
  • Raphael Kopan · Shuang Chen · Melissa Little
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    ABSTRACT: Within the developing mammalian kidney, several populations of progenitors form the discrete cellular components of the final organ. Fate mapping experiments revealed the cap mesenchyme (CM) to be the progenitor population for all nephron epithelial cells, whereas the neighboring stromal mesenchyme gives rise to mesangial, pericytic, renin-producing and interstitial cells. The collecting ducts are derived from a population of progenitors at the ureteric bud (UB) tip and a proportion of the endothelium is also derived from a dedicated mesenchymal progenitor. The stroma, CM, and UB interact to create spatially defined niches at the periphery of the developing organ. While the UB tip population persist, the CM represents a transient progenitor population that is exhausted to set the final organ size. The timing of CM exhaustion, and hence the final organ structure, is sensitive to disruptions such as premature birth. Here we will discuss our current understanding of the molecular processes allowing these populations to balance cell survival, self-renewal, support of branching, and maintain capacity to commit to differentiation.
    Current Topics in Developmental Biology 01/2014; 107C:293-331. DOI:10.1016/B978-0-12-416022-4.00011-1 · 4.68 Impact Factor
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    ABSTRACT: The interactions between the nephrogenic mesenchyme and the ureteric bud during kidney development are well documented. While recent studies have shed some light on the importance of the stroma during renal development, many of the signals generated in the stroma, the genetic pathways and interaction networks involving the stroma are yet to be identified. Our previous studies demonstrate that retinoids are crucial for branching of the ureteric bud and for patterning of the cortical stroma. In the present study we demonstrate that autocrine retinoic acid (RA) signaling in stromal cells is critical for their survival and patterning, and show that Extracellular matrix 1, Ecm1, a gene that in humans causes irritable bowel syndrome and lipoid proteinosis, is a novel RA-regulated target in the developing kidney, which is secreted from the cortical stromal cells surrounding the cap mesenchyme and ureteric bud. Our studies suggest that Ecm1 is required in the ureteric bud for regulating the distribution of Ret which is normally restricted to the tips, as inhibition of Ecm1 results in an expanded domain of Ret expression and reduced numbers of branches. We propose a model in which retinoid signaling in the stroma activates expression of Ecm1, which in turn down-regulates Ret expression in the ureteric bud cleft, where bifurcation normally occurs and normal branching progresses.
    PLoS ONE 12/2013; 8(12):e84155. DOI:10.1371/journal.pone.0084155 · 3.23 Impact Factor
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    ABSTRACT: The Kidney Research National Dialogue represents a novel effort by the National Institute of Diabetes and Digestive and Kidney Diseases to solicit and prioritize research objectives from the renal research and clinical communities. The present commentary highlights selected scientific opportunities specific to the study of renal development, physiology, and cell biology. Describing such fundamental kidney biology serves as a necessary foundation for translational and clinical studies that will advance disease care and prevention. It is intended that these objectives foster and focus scientific efforts in these areas in the coming decade and beyond.
    Clinical Journal of the American Society of Nephrology 12/2013; 9(4). DOI:10.2215/CJN.10851013 · 4.61 Impact Factor

Publication Stats

5k Citations
863.66 Total Impact Points


  • 2015
    • University of Melbourne
      • Department of Paediatrics
      Melbourne, Victoria, Australia
    • Murdoch Childrens Research Institute
      Melbourne, Victoria, Australia
  • 1992–2015
    • University of Queensland
      • • Institute for Molecular Bioscience
      • • Division of Molecular Genetics and Development
      • • Division of Molecular Cell Biology
      Brisbane, Queensland, Australia
  • 2014
    • Washington University in St. Louis
      • Department of Developmental Biology
      San Luis, Missouri, United States
  • 2006–2007
    • Monash University (Australia)
      • • Department of Physiology
      • • Monash Immunology and Stem Cell Laboratories (MISCL)
      Melbourne, Victoria, Australia
  • 2004
    • Nara Institute of Science and Technology
      Ikuma, Nara, Japan
  • 1988–2000
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia
  • 1992–1999
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 1987
    • Royal Children's Hospital Brisbane
      Brisbane, Queensland, Australia