Yu, J. et al. A Wnt7b-dependent pathway regulates the orientation of epithelial cell division and establishes the cortico-medullary axis of the mammalian kidney. Development 136, 161-171

Department of Molecular and Cellular Biology and Harvard Stem Cell Institute, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
Development (Impact Factor: 6.46). 02/2009; 136(1):161-71. DOI: 10.1242/dev.022087
Source: PubMed


The mammalian kidney is organized into a cortex where primary filtration occurs, and a medullary region composed of elongated tubular epithelia where urine is concentrated. We show that the cortico-medullary axis of kidney organization and function is regulated by Wnt7b signaling. The future collecting duct network specifically expresses Wnt7b. In the absence of Wnt7b, cortical epithelial development is normal but the medullary zone fails to form and urine fails to be concentrated normally. The analysis of cell division planes in the collecting duct epithelium of the emerging medullary zone indicates a bias along the longitudinal axis of the epithelium. By contrast, in Wnt7b mutants, cell division planes in this population are biased along the radial axis, suggesting that Wnt7b-mediated regulation of the cell cleavage plane contributes to the establishment of a cortico-medullary axis. The removal of beta-catenin from the underlying Wnt-responsive interstitium phenocopies the medullary deficiency of Wnt7b mutants, suggesting a paracrine role for Wnt7b action through the canonical Wnt pathway. Wnt7b signaling is also essential for the coordinated growth of the loop of Henle, a medullary extension of the nephron that elongates in parallel to the collecting duct epithelium. These findings demonstrate that Wnt7b is a key regulator of the tissue architecture that establishes a functional physiologically active mammalian kidney.

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    • "The ectopic expression of the proapoptotic protein, Bim, and elevated levels of downstream p53 effector genes (Bax, Trp53inp1, Jun and Cd- kn1a) in FoxD1 GC ;Dicer fl/fl kidneys support the idea that misregulated apoptosis contributes to the renal pheno- type. The renal stroma has been shown to play crucial roles in many aspects of kidney development, including modulation of nephron progenitor self-renewal and differentiation , as well as establishment of the cortico-medullary axis (Yu et al. 2009; Das et al. 2013). Although Nakagawa et al. (2015) reported decreased nephron progenitors in FoxD1 GC ;Dicer fl/fl kidneys, we have several experimental lines of evidence that support an expansion of this population in our model, including immunofluorescence, microarray data, and quantitative real-time PCR for nephron progenitor-specific genes. "
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    ABSTRACT: MicroRNAs are small noncoding RNAs that post-transcriptionally regulate mRNA levels. While previous studies have demonstrated that miRNAs are indispensable in the nephron progenitor and ureteric bud lineage, little is understood about stromal miRNAs during kidney development. The renal stroma (marked by expression of FoxD1) gives rise to the renal interstitium, a subset of peritubular capillaries, and multiple supportive vascular cell types including pericytes and the glomerular mesangium. In this study, we generated FoxD1(GC);Dicer(fl/fl) transgenic mice that lack miRNA biogenesis in the FoxD1 lineage. Loss of Dicer activity resulted in multifaceted renal anomalies including perturbed nephrogenesis, expansion of nephron progenitors, decreased renin-expressing cells, fewer smooth muscle afferent arterioles, and progressive mesangial cell loss in mature glomeruli. Although the initial lineage specification of FoxD1(+) stroma was not perturbed, both the glomerular mesangium and renal interstitium exhibited ectopic apoptosis, which was associated with increased expression of Bcl2l11 (Bim) and p53 effector genes (Bax, Trp53inp1, Jun, Cdkn1a, Mmp2, and Arid3a). Using a combination of high-throughput miRNA profiling of the FoxD1(+)-derived cells and mRNA profiling of differentially expressed transcripts in FoxD1(GC);Dicer(fl/fl) kidneys, at least 72 miRNA:mRNA target interactions were identified to be suppressive of the apoptotic program. Together, the results support an indispensable role for stromal miRNAs in the regulation of apoptosis during kidney development.
    10/2015; 3(10). DOI:10.14814/phy2.12537
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    • "As expected, some Foxd1+ maturing podocytes were labeled such that all podocytes were b-gal+ in the adult kidney (black arrowheads in Figures 2E, 2F, and S4C; data not shown). In the renal medulla, a subset of medullary interstitial cells expressing CDKN1C+ (P57KIP2+) (Yu et al., 2009; Zhang et al., 1997) was b-gal+ (Figure 2G), but F4/80+ macrophages were b-galÀ (Figure 2H). Although SMA+ cells in the kidney were derived from Foxd1+ cells, b-gal+ cells were not observed in the SMA+ smooth muscle of the ureter (Figure 2I). "
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    ABSTRACT: The mammalian kidney is a complex organ consisting of multiple cell types. We previously showed that the Six2-expressing cap mesenchyme is a multipotent self-renewing progenitor population for the main body of the nephron, the basic functional unit of the kidney. However, the cellular mechanisms establishing stromal tissues are less clear. We demonstrate that the Foxd1-expressing cortical stroma represents a distinct multipotent self-renewing progenitor population that gives rise to stromal tissues of the interstitium, mesangium, and pericytes throughout kidney organogenesis. Fate map analysis of Foxd1-expressing cells demonstrates that a small subset of these cells contributes to Six2-expressing cells at the early stage of kidney outgrowth. Thereafter, there appears to be a strict nephron and stromal lineage boundary derived from Six2-expressing and Foxd1-expressing cell types, respectively. Taken together, our observations suggest that distinct multipotent self-renewing progenitor populations coordinate cellular differentiation of the nephron epithelium and renal stroma during mammalian kidney organogenesis.
    Stem Cell Reports 10/2014; 3(4). DOI:10.1016/j.stemcr.2014.08.008 · 5.37 Impact Factor
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    • "In particular, it fails to account for two features: it would not produce the long, straight collecting ducts that run almost parallel through the medulla, and it would not have large numbers of tubules converging at the papillae rather than meeting in a spaced, sequential way all the way down a tree (Kim et al. 2002). Suggested explanations for the existence of long medullary ducts have included selective longitudinal growth, in particular by orientated cell division, and convergent extension movements (Cebri an et al. 2004; Yu et al. 2009; Costantini & Kopan, 2010; Costantini, 2012). Convergence at the medulla is more difficult to explain this way: this has generally been assumed to result from an expansion of the renal pelvis in a way that obliterates early branch points (Potter, 1972). "
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    ABSTRACT: This report presents a novel mechanism for remodelling a branched epithelial tree. The mouse renal collecting duct develops by growth and repeated branching of an initially unbranched ureteric bud: this mechanism initially produces an almost fractal form with young branches connected to the centre of the kidney via a sequence of nodes (branch points) distributed widely throughout the developing organ. The collecting ducts of a mature kidney have a different form: from the nephrons in the renal cortex, long, straight lengths of collecting duct run almost parallel to one another through the renal medulla, and open together to the renal pelvis. Here we present time-lapse studies of E11.5 kidneys growing in culture: after about 5 days, the collecting duct trees show evidence of ‘node retraction’, in which the node of a ‘Y’-shaped branch moves downwards, shortening the stalk of the ‘Y’, lengthening its arms and narrowing their divergence angle so that the ‘Y’ becomes a ‘V’. Computer simulation suggests that node retraction can transform a spread tree, like that of an early kidney, into one with long, almost-parallel medullary rays similar to those seen in a mature real kidney.
    Journal of Anatomy 10/2014; 226(1). DOI:10.1111/joa.12239 · 2.10 Impact Factor
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