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Branching morphogenesis is an integral developmental mechanism central to the formation of a range of organs including the kidney, lung, pancreas and mammary gland. The ramified networks of epithelial tubules it establishes are critical for the processes of secretion, excretion and exchange mediated by these tissues. In the kidney, branching serves to establish the collecting duct system that transports urine from the nephrons into the renal pelvis, ureter and finally the bladder. Generally speaking, the formation of these networks in different organs begins with the specification and differentiation of simple bud-like organ anlage, which then undergo a process of elaboration, typically by bifurcation. This process is often governed by the interaction of progenitor cells at the tips of the epithelia with neighboring mesenchymal cell populations which direct the branching process and which often themselves differentiate to form part of the adult organ. In the kidney, the tips of ureteric bud elaborate through a dynamic cell signaling relationship with overlying nephron progenitor cell populations. These cells sequentially commit to differentiation and the resulting nephrons reintegrate with the ureteric epithelium as development progresses. This review will describe recent advances in understanding the how the elaboration of the ureteric bud is patterned and consider the extent to which this process is shared with other organs., (© 2020 American Association for Anatomy.)

Adamts18 encodes a secreted metalloprotease restricted to branch-tip progenitor pools directing the morphogenesis of multiple mammalian organs. Adamts18 was targeted to explore a potential role in branching morphogenesis. In the kidney, an arborized collecting system develops through extensive branching morphogenesis of an initial epithelial outgrowth of the mesonephric duct, the ureteric bud. Adamts18 mutants displayed a weakly penetrant phenotype: duplicated ureteric outgrowths forming enlarged, bi-lobed kidneys with an increased nephron endowment. In contrast, Adamts18 mutants showed a fully penetrant lung phenotype: epithelial growth was markedly reduced and early secondary branching scaled to the reduced length of the primary airways. Furthermore, there was a pronounced delay in the appearance of differentiated cell types in both proximal and distally positions of the developing airways. Adamts18 is closely related to Adamts16. In the kidney but not the lung, broad epithelial Adamts16 expression overlaps Adamts18 in branch tips. However, compound Adamts16/18 mutants displayed a comparable low penetrance duplicated ureteric phenotype, ruling out a possible role for Adamts16 as a functional modifier of the Adamts18 kidney phenotype. Given the predicted action of secreted Adamts18 metalloprotease, and broad expression of Adamts18 in branching organ systems, these findings suggest distinct requirements for matrix modelling in the morphogenesis of epithelial networks., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (© 2018 Wiley Periodicals, Inc.)

A normal endowment of nephrons in the mammalian kidney requires a balance of nephron progenitor self-renewal and differentiation throughout development. Here, we provide evidence for a novel action of ureteric branch tip-derived Wnt11 in progenitor cell organization and interactions within the nephrogenic niche, ultimately determining nephron endowment. In Wnt11 mutants, nephron progenitors dispersed from their restricted niche, intermixing with interstitial progenitors. Nephron progenitor differentiation was accelerated, kidneys were significantly smaller, and the nephron progenitor pool was prematurely exhausted, halving the final nephron count. Interestingly, RNA-seq revealed no significant differences in gene expression. Live imaging of nephron progenitors showed that in the absence of Wnt11 they lose stable attachments to the ureteric branch tips, continuously detaching and reattaching. Further, the polarized distribution of several markers within nephron progenitors is disrupted. Together these data highlight the importance of Wnt11 signaling in directing nephron progenitor behavior which determines a normal nephrogenic program., Competing Interests: LO, AC, KS, NL, PW, LC, AJ, AA, OM, JB, IS, ML, AM No competing interests declared, (© 2018, O'Brien et al.)

Branching morphogenesis of the ureteric bud is integral to kidney development; establishing the collecting ducts of the adult organ and driving organ expansion via peripheral interactions with nephron progenitor cells. A recent study suggested that termination of tip branching within the developing kidney involved stochastic exhaustion in response to nephron formation, with such a termination event representing a unifying developmental process evident in many organs. To examine this possibility, we have profiled the impact of nephron formation and maturation on elaboration of the ureteric bud during mouse kidney development. We find a distinct absence of random branch termination events within the kidney or evidence that nephrogenesis impacts the branching program or cell proliferation in either tip or progenitor cell niches. Instead, organogenesis proceeds in a manner indifferent to the development of these structures. Hence, stochastic cessation of branching is not a unifying developmental feature in all branching organs., Competing Interests: KS, AC, VL, JL, LJ, NH, IS No competing interests declared, ML has consulted for and received research funding from Organovo Inc., (© 2018, Short et al.)

The mammalian kidney develops from a simple epithelial bud to an arborized network of tubules, which are fated to form the ureter, renal pelvis and collecting ducts. This process of ductal elaboration is achieved through an ancient developmental mechanism known as branching morphogenesis that is widely employed in glandular organs, the vasculature and lungs. It breaks up large solid tissues facilitating secretion, excretion and gas exchange, depending on the tissue. In the kidney, growth of the ureteric bud is driven by interactions between progenitor cells in the tips of the epithelial tree and their mesenchymal 'caps'. The cells of the cap mesenchyme give rise to nephrons; therefore, the interaction between these two cell populations is likely to be a critical driver of nephron number, which is determined during gestation. These cellular interactions are potentially affected by genetic mutations (congenital kidney diseases) and by changes in the fetal environment. Understanding the aetiology of congenital and acquired kidney diseases therefore requires a full appreciation of the processes involved in establishing the cellular architecture of the kidney and of the factors that affect the commitment of progenitor cells to form nephrons.

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., (Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.)