Genetic mosaic analysis reveals a major role for frizzled 4 and frizzled 8 in controlling ureteric growth in the developing kidney
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Development
(Impact Factor: 6.46).
03/2011; 138(6):1161-72. DOI: 10.1242/dev.057620
The developing mammalian kidney is an attractive system in which to study the control of organ growth. Targeted mutations in the Wnt receptors frizzled (Fz) 4 and Fz8 lead to reduced ureteric bud growth and a reduction in kidney size, a phenotype previously reported for loss of Wnt11. In cell culture, Fz4 and Fz8 can mediate noncanonical signaling stimulated by Wnt11, but only Fz4 mediates Wnt11-stimulated canonical signaling. In genetically mosaic mouse ureteric buds, competition between phenotypically mutant Fz4(-/-) or Fz4(-/-);Fz8(-/-) cells and adjacent phenotypically wild-type Fz4(+/-) or Fz4(+/-);Fz8(-/-) cells results in under-representation of the mutant cells to an extent far greater than would be predicted from the size reduction of homogeneously mutant kidneys. This discrepancy presumably reflects the compensatory action of a network of growth regulatory systems that minimize developmental perturbations. The present work represents the first description of a kidney phenotype referable to one or more Wnt receptors and demonstrates a general strategy for revealing the contribution of an individual growth regulatory pathway when it is part of a larger homeostatic network.
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- "Additionally, we identified a profound loss of the medullary zone and of tubular bundles in Vangl2 mutants, indicating potential defects in tubular elongation (Figure 2(b)). Ye et al. described substantial renal hypoplasia (no sign of dysplasia) in targeted combined Fz4−/−; Fz8−/− mutants . Both Fz4 and Fz8 participate in the PCP signaling and are expressed exclusively in UB branches. "
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ABSTRACT: The evolutionarily conserved planar cell polarity (PCP) signaling pathway controls tissue polarity within the plane orthogonal to the apical-basal axis. PCP was originally discovered in Drosophila melanogaster where it is required for the establishment of a uniform pattern of cell structures and appendages. In vertebrates, including mammals, the PCP pathway has been adapted to control various morphogenetic processes that are critical for tissue and organ development. These include convergent extension (crucial for neural tube closure and cochlear duct development) and oriented cell division (needed for tubular elongation), ciliary tilting that enables directional fluid flow, and other processes. Recently, strong evidence has emerged to implicate the PCP pathway in vertebrate kidney development. In this review, we will describe the experimental data revealing the role of PCP signaling in nephrogenesis and kidney disease.
Available from: Kimmo Halt
- "Wnt11 may signal via fz4 since this combination activates the TFC/Lef and the Rho reporters in cell culture. Concurrent expression of Wnt11 and Fz8 activates Rho suggesting specific mode of signaling via the frizzled subclasses . Thus, Fz4 and Fz8 may act in synergy to transduce Wnt11 signaling and promote UB branching. "
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ABSTRACT: Several Wnt proteins are expressed in the embryonic kidney during various stages of development. Gene knockout models and ex vivo studies have provided strong evidence that Wnt-mediated signals are essential in renal ontogeny. Perhaps the most critical factors, Wnt9b and Wnt4, function during the early phase when the cap mesenchyme is induced to undergo morphogenesis into a nephron. Wnt11 controls early ureteric bud branching and contributes to the final kidney size. In addition to its inductive role, later on Wnt9b plays a significant role in the convergent extension of the tubular epithelial cells, while Wnt4 signaling controls smooth muscle cell fates in the medulla. Wnt7b has a specific function together with its likely antagonist Dkk1 in controlling the morphogenesis of the renal medulla. The signal-transduction mechanisms of the Wnts in kidney ontogeny have not been resolved, but studies characterizing the downstream signaling pathways are emerging. Aberrant Wnt signaling may lead to kidney diseases ranging from fatal kidney agenesis to more benign phenotypes. Wnt-mediated signaling regulates several critical aspects of kidney development from the early inductive stages to later steps of tubular epithelial maturation.
Available from: Andrew J Copp
- "E13.5 and E18.5 Vangl2Lp/Lp kidneys were also smaller than wild-type littermates , especially in their antero-posterior axis with a lower length/width ratio. Knock-out mice of other PCP genes (Dchs1, Fat4 and double mutants for both Fz4 and Fz8) also have impaired ureteric bud branching compared with wild-type littermates and smaller kidneys at birth [24, 25]. In addition, mice with mutations in Wnt ligands thought to signal through the PCP pathway (Wnt7b, Wnt9b and Wnt11) also exhibit ureteric bud branching defects [26–28]. "
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ABSTRACT: Planar cell polarity (PCP) is the uniform orientation and alignment of a group of cells orthogonal to the apical–basal axis
within a tissue. Originally described in insects, it is now known that PCP is required for many processes in vertebrates,
including directional cell movement, polarized cell division, ciliary orientation, neural tube closure, heart development
and lung branching. In this review, we outline the evidence implicating PCP in kidney development and disease focusing initially
on the function of PCP in ureteric bud branching and elongation. We then describe how defects in PCP may lead to polycystic
kidney disease and discuss a newly identified role for PCP in the kidney filtration barrier.
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