Genetic mosaic analysis reveals a major role for frizzled 4 and frizzled 8 in controlling ureteric growth in the developing kidney.
ABSTRACT 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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ABSTRACT: Canonical WNT signaling is required for proper vascularization of the CNS during embryonic development. Here, we used mice with targeted mutations in genes encoding canonical WNT pathway members to evaluate the exact contribution of these components in CNS vascular development and in specification of the blood-brain barrier (BBB) and blood-retina barrier (BRB). We determined that vasculature in various CNS regions is differentially sensitive to perturbations in canonical WNT signaling. The closely related WNT signaling coreceptors LDL receptor-related protein 5 (LRP5) and LRP6 had redundant functions in brain vascular development and barrier maintenance; however, loss of LRP5 alone dramatically altered development of the retinal vasculature. The BBB in the cerebellum and pons/interpeduncular nuclei was highly sensitive to decrements in canonical WNT signaling, and WNT signaling was required to maintain plasticity of barrier properties in mature CNS vasculature. Brain and retinal vascular defects resulting from ablation of Norrin/Frizzled4 signaling were ameliorated by stabilizing β-catenin, while inhibition of β-catenin-dependent transcription recapitulated the vascular development and barrier defects associated with loss of receptor, coreceptor, or ligand, indicating that Norrin/Frizzled4 signaling acts predominantly through β-catenin-dependent transcriptional regulation. Together, these data strongly support a model in which identical or nearly identical canonical WNT signaling mechanisms mediate neural tube and retinal vascularization and maintain the BBB and BRB.Journal of Clinical Investigation 08/2014; · 13.77 Impact Factor
Article: The Kidney and Planar Cell Polarity.[Show abstract] [Hide abstract]
ABSTRACT: Planar cell polarity (PCP) or tissue polarity describes a coordinated polarity at the plane of the tissue where most or all cells within a tissue are polarized in one direction. It is perpendicular to the apical-basal polarity of the cell. PCP is manifested readily in the Drosophila wing and cuticle bristles, Drosophila eye ommatidia, and mammalian hair and inner ear hair bundles, and less evidently, in cellular processes such as in the coordinated, directional cell movements, and oriented cell divisions that are important for tissue morphogenesis. Several distinct molecular and cellular processes have been implicated in the regulation of PCP. Here, we review potential roles for PCP during mouse kidney development and maintenance, including ureteric bud branching morphogenesis, renal medulla elongation, tubule diameter establishment/maintenance, glomerulogenesis, and response to injury. The potential mechanisms underlying these processes, including oriented cell division and coordinated cell migration/cell intercalation, are discussed. In addition, we discuss some unaddressed research topics related to PCP in the kidney that we hope will spur further discussion and investigation.Current Topics in Developmental Biology 01/2012; 101C:185-212. · 4.21 Impact Factor
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ABSTRACT: Ovarian cancer (OvCa) metastasizes to organs in the abdominal cavity, such as the omentum, which are covered by a single layer of mesothelial cells. Mesothelial cells are generally thought to be "bystanders" to the metastatic process and simply displaced by OvCa cells to access the submesothelial extracellular matrix. Here, using organotypic 3D cultures, we found that primary human mesothelial cells secrete fibronectin in the presence of OvCa cells. Moreover, we evaluated the tumor stroma of 108 human omental metastases and determined that fibronectin was consistently overexpressed in these patients. Blocking fibronectin production in primary mesothelial cells in vitro or in murine models, either genetically (fibronectin 1 floxed mouse model) or via siRNA, decreased adhesion, invasion, proliferation, and metastasis of OvCa cells. Using a coculture model, we determined that OvCa cells secrete TGF-β1, which in turn activates a TGF-β receptor/RAC1/SMAD-dependent signaling pathway in the mesothelial cells that promotes a mesenchymal phenotype and transcriptional upregulation of fibronectin. Additionally, blocking α5 or β1 integrin function with antibodies reduced metastasis in an orthotopic preclinical model of OvCa metastasis. These findings indicate that cancer-associated mesothelial cells promote colonization during the initial steps of OvCa metastasis and suggest that mesothelial cells actively contribute to metastasis.Journal of Clinical Investigation 09/2014; · 13.77 Impact Factor