Angioblast-mesenchyme induction of early kidney development is mediated by Wt1 and Vegfa

Harvard University, Cambridge, Massachusetts, United States
Development (Impact Factor: 6.27). 01/2006; 132(24):5437-49. DOI: 10.1242/dev.02095
Source: PubMed

ABSTRACT Most studies on kidney development have considered the interaction of the metanephric mesenchyme and the ureteric bud to be the major inductive event that maintains tubular differentiation and branching morphogenesis. The mesenchyme produces Gdnf, which stimulates branching, and the ureteric bud stimulates continued growth of the mesenchyme and differentiation of nephrons from the induced mesenchyme. Null mutation of the Wt1 gene eliminates outgrowth of the ureteric bud, but Gdnf has been identified as a target of Pax2, but not of Wt1. Using a novel system for microinjecting and electroporating plasmid expression constructs into murine organ cultures, it has been demonstrated that Vegfa expression in the mesenchyme is regulated by Wt1. Previous studies had identified a population of Flk1-expressing cells in the periphery of the induced mesenchyme, and adjacent to the stalk of the ureteric bud, and that Vegfa was able to stimulate growth of kidneys in organ culture. Here it is demonstrated that signaling through Flk1 is required to maintain expression of Pax2 in the mesenchyme of the early kidney, and for Pax2 to stimulate expression of Gdnf. However, once Gdnf stimulates branching of the ureteric bud, the Flk1-dependent angioblast signal is no longer required to maintain branching morphogenesis and induction of nephrons. Thus, this work demonstrates the presence of a second set of inductive events, involving the mesenchymal and angioblast populations, whereby Wt1-stimulated expression of Vegfa elicits an as-yet-unidentified signal from the angioblasts, which is required to stimulate the expression of Pax2 and Gdnf, which in turn elicits an inductive signal from the ureteric bud.

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    • "Several genes, with specific expression in the periureteric mesenchyme, have been shown to depend upon Tbx18: among them, SOX9 is required for correct differentiation of the ureteric smooth muscle layer (Kispert et al., 1998). Angioblast mesenchyme induction during early kidney development is mediated by VEGF-A, which appears to act on the angioblast population under WT1 control (Gao et al., 2005). "
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    ABSTRACT: The development of the human kidney is a complex process that requires interactions between epithelial and mesenchymal cells, eventually leading to the coordinated growth and differentiation of multiple highly specialized stromal, vascular, and epithelial cell types. The application of molecular biology and immunocytochemistry to the study of cell types involved in renal morphogenesis is leading to a better understanding of nephrogenesis, which requires a fine balance of many factors that can be disturbed by various prenatal events in humans. The aim of this paper is to review human kidney organogenesis, with particular emphasis on the sequence of morphological events, on the immunohistochemical peculiarities of nephron progenitor populations and on the molecular pathways regulating the process of mesenchymal to epithelial transition. Kidney development can be subdivided into five steps: (i) the primary ureteric bud (UB); (ii) the cap mesenchyme; (iii) the mesenchymal–epithelial transition; (iv) glomerulogenesis and tubulogenesis; (v) the interstitial cells. Complex correlations between morphological and molecular events from the origin of the UB and its branching to the metanephric mesenchyme, ending with the maturation of nephrons, have been reported in different animals, including mammals. Marked differences, observed among different species in the origin and the duration of nephrogenesis, suggest that morphological and molecular events may be different in different animal species and mammals. Further studies must be carried out in humans to verify at the morphological, immunohistochemical, and molecular levels if the outcome in humans parallels that previously described in other species. J. Cell. Physiol. 227: 1257–1268, 2012. © 2011 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 03/2012; 227(3):1257 - 1268. DOI:10.1002/jcp.22985 · 3.87 Impact Factor
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    • "contains foxd1+ and flk1+ progenitors that differentiate into the renal stroma and endothelia, respectively (Hatini et al., 1996; Humphreys et al., 2008; Shalaby et al., 1995; Tufro et al., 1999). In vitro experiments and gene ablation studies suggest that factors secreted by these stromal and endothelial progenitor cell populations are also required for renal morphogenesis (Bard, 1996; Hatini et al., 1996; Sariola et al., 1988a; Gao et al., 2005; Levinson et al., 2005; Quaggin et al., 1999) . Thus, signaling between several distinct progenitor cell populations within the metanephric rudiment controls kidney development. "
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    ABSTRACT: The development of most, if not all, tubular organs is dependent on signaling between epithelial and stromal progenitor populations. Most often, these lineages derive from different germ layers that are specified during gastrulation, well in advance of organ condensation. Thus, one of the first stages of organogenesis is the integration of distinct progenitor populations into a single embryonic rudiment. In contrast, the stromal and epithelial lineages controlling renal development are both believed to derive from the intermediate mesoderm and to be specified as the kidney develops. In this study we directly analyzed the lineage of renal epithelia and stroma in the developing chick embryo using two independent fate mapping techniques. Results of these experiments confirm the hypothesis that nephron epithelia derive from the intermediate mesoderm. Most importantly, we discovered that large populations of renal stroma originate in the paraxial mesoderm. Collectively, these studies suggest that the signals that subdivide mesoderm into intermediate and paraxial domains may play a role in specifying nephron epithelia and a renal stromal lineage. In addition, these fate mapping data indicate that renal development, like the development of all other tubular organs, is dependent on the integration of progenitors from different embryonic tissues into a single rudiment.
    Developmental Biology 04/2009; 329(2):169-75. DOI:10.1016/j.ydbio.2009.02.034 · 3.64 Impact Factor
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    • "These data further support the growing idea that Vegf has extra-endothelial roles. However, it should be noted that these data do not negate the earlier findings that provide evidence for alternate mechanisms (via endothelial cells or their precursors) for the actions of Vegf on epithelial tissues (Gao et al., 2005; Tufro et al., 2007a). "
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    ABSTRACT: There is growing evidence that vascular endothelial growth factor (Vegf), a well-recognized angiogenic factor, plays a regulatory role in non-endothelial tissues such as neurons and epithelial cells. In the kidney Vegf receptors have been detected in proximal tubule cells of the adult kidney and Vegf has been show to stimulate branching morphogenesis of the developing kidney. In this study, using laser-microdissection as well as manual separation of the UB, we demonstrate that Vegf receptors are present in the ureteric bud (UB). Furthermore, we determine that Vegf stimulates UB branching in whole kidney explant that is mediated directly by signaling through Vegfr2. In addition, Vegf also induced branching response in isolated UBs that are free of the surrounding mesenchyme. These responses seem to be strictly dependent on the dose of Vegf such that higher doses are inhibitory while lower dose are stimulatory. These data place Vegf in a unique position of being able to modulate vascular as well as epithelial development in the embryonic kidney.
    Mechanisms of development 03/2009; 126(3-4):91-8. DOI:10.1016/j.mod.2008.12.003 · 2.24 Impact Factor
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