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: Wnt genes and components of Wnt signalling pathways have been implicated in a wide spectrum of important biological phenomena, ranging from early organismal development to cell behaviours to several diseases, especially cancers. Emergence of the field of Wnt signalling can be largely traced back to the discovery of the first mammalian Wnt gene in 1982. In this essay, we mark the thirtieth anniversary of that discovery by describing some of the critical scientific developments that led to the flowering of this field of research.The EMBO Journal 05/2012; 31(12):2670-84. DOI:10.1038/emboj.2012.146 · 10.75 Impact Factor
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ABSTRACT: Genetic studies of Wnt11 have revealed many insights into the roles and regulation of Wnt11, particularly during development. New tools to study Wnt11 have recently become available, making it timely to review the literature regarding this unique Wnt family member. In this study, we focus on mammalian Wnt11, describing its main sites of expression during development, and how the Wnt11 gene is regulated. We highlight an emerging theme in which canonical Wnt signals regulate Wnt11 expression through transcription factors in addition to, or other than, Tcf/LEF family members. We also discuss the frizzled family and other receptors that bind to Wnt11, the intracellular kinases and small GTPases that act downstream of Wnt11, and the effects of Wnt11 on Wnt/β-catenin signalling. Finally, we elaborate on the relevance of Wnt11 to human cancer, where it appears to be important both for proliferation and/or survival during normal differentiation and for migration/invasion.Acta Physiologica 03/2011; 204(1):52-64. DOI:10.1111/j.1748-1716.2011.02297.x · 4.25 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. DOI:10.1016/B978-0-12-394592-1.00011-9 · 4.21 Impact Factor