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Cellular and molecular determinants of normal and abnormal kidney development

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Kidneys are bilateral organs required to maintain homeostasis in the body through the regulation of fluid composition and the excretion of metabolic waste products. The initial steps in organ development are characterized by cellular interactions which regulate both the position and number of kidneys formed. Once established, further development is driven by orchestrated interactions between progenitor cell populations which serve to establish both nephrons—the functional unit of the organ which filters the blood—and the complex ramified collecting duct system which transports urine to the bladder. The delicate balance involved in these processes is reflected in the emerging family of genetic or environmental factors which, when perturbed, give rise to defects in organ development or function later in life. This article is categorized under: Vertebrate Organogenesis > From a Tubular Primordium: Branched Birth Defects > Organ Anomalies
Schematic representation of kidney development which occurs at fourth week of gestation in human and E10.5 in mice. (a) The ureteric bud (UB) emanates from the nephric duct (ND) and elongates towards an adjacent group of mesenchymal cells called the metanephric mesenchyme (MM). (b) Upon invasion of UB into MM, the reciprocal interaction between both structures results in the commencement of metanephric kidney development. (c) The UB in contact with MM undergoes multiple rounds of branching morphogenesis to form the collecting duct system, while a subset of nephron progenitor cells in the MM aggregates around the UB to form the cap mesenchyme. The cap mesenchyme will epithelialize to form a renal vesical and subsequently develop into a nephron which facilitates filtration in the kidney. The UB outside of the MM elongates and develops into a ureter which matures and differentiates into four layers of cells: urothelium (Uro), stromal cells (Stm), smooth muscle cells (SM) and adventitial fibroblasts (AF)
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List of environmental factors which alters renal developmental at a molecular or cellular level, in a range of CAKUT phenotypes
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Schematic overview of major proteins and signaling pathways involved in ureteric bud (UB) outgrowth. This process is centered around GDNF interaction with its receptor RET. RET is expressed in the UB (green) and GDNF is secreted by the metanephric mesenchyme (red). The coordination of other major genes/signaling pathways also plays a crucial role in the outgrowth of UB by inducing or repressing GDNF/RET signaling and mutation in any of these proteins will lead to defects in UB induction
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Different forms of CAKUT caused by defects in ureteric bud (UB) outgrowth. (a) During normal kidney and ureter development, UB emanates from the nephric duct (ND) and interacts with the metanephric mesenchyme (MM). The common nephric duct (CND) which is located at the caudal segment of the ND, integrates into the urogenital sinus (the future bladder) and undergoes apoptosis. This establishes a patent direct connection between the ureters and the bladder which, with urethral orifice, forms a triangular region called the trigone. (b) Failure of UB outgrowth from the ND causes MM to undergo apoptosis (due to lack of reciprocal interaction) and results in renal agenesis. (c) Formation of multiple UBs are associated with abnormal renal and ureter phenotypes including multicystic kidney, dysplastic kidney, duplex kidney, and duplex ureter. (d) Mislocalized UB outgrowth is associated with mispositioned ureteric orifice and defective valve at the ureterovesical junction (UVJ) hence causing vesicoureteral reflux (VUR) and subsequently hydronephrosis
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Reciprocal interactions between the ureteric bud (UB) and metanephric mesenchyme (MM) is crucial for metanephric development. The UB induces MM to form horseshoe‐shaped aggregates called the cap mesenchyme (SIX2, red) which establishes points of contact with the UB tips (TROP2, cyan). Images were taken from an E19.5 fetal mouse kidney
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Vertebrate Organogenesis > From a Tubular Primordium: Branched
Birth Defects > Organ Anomalies