Pygo1 and Pygo2 roles in Wnt signaling in mammalian kidney development

Division of Developmental Biology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
BMC Biology (Impact Factor: 7.98). 04/2007; 5(1):15. DOI: 10.1186/1741-7007-5-15
Source: PubMed


The pygopus gene of Drosophila encodes an essential component of the Armadillo (beta-catenin) transcription factor complex of canonical Wnt signaling. To better understand the functions of Pygopus-mediated canonical Wnt signaling in kidney development, targeted mutations were made in the two mammalian orthologs, Pygo1 and Pygo2.
Each mutation deleted >80% of the coding sequence, including the critical PHD domain, and almost certainly resulted in null function. Pygo2 homozygous mutants, with rare exception, died shortly after birth, with a phenotype including lens agenesis, growth retardation, altered kidney development, and in some cases exencephaly and cleft palate. Pygo1 homozygous mutants, however, were viable and fertile, with no detectable developmental defects. Double Pygo1/Pygo2 homozygous mutants showed no apparent synergy in phenotype severity. The BAT-gal transgene reporter of canonical Wnt signaling showed reduced levels of expression in Pygo1-/-/Pygo2-/- mutants, with tissue-specific variation in degree of diminution. The Pygo1 and Pygo2 genes both showed widespread expression in the developing kidney, with raised levels in the stromal cell compartment. Confocal analysis of the double mutant kidneys showed disturbance of both the ureteric bud and metanephric mesenchyme-derived compartments. Branching morphogenesis of the ureteric bud was altered, with expanded tips and reduced tip density, probably contributing to the smaller size of the mutant kidney. In addition, there was an expansion of the zone of condensed mesenchyme capping the ureteric bud. Nephron formation, however, proceeded normally. Microarray analysis showed changed expression of several genes, including Cxcl13, Slc5a2, Klk5, Ren2 and Timeless, which represent candidate Wnt targets in kidney development.
The mammalian Pygopus genes are required for normal branching morphogenesis of the ureteric bud during kidney development. Nevertheless, the relatively mild phenotype observed in the kidney, as well as other organ systems, indicates a striking evolutionary divergence of Pygopus function between mammals and Drosophila. In mammals, the Pygo1/Pygo2 genes are not absolutely required for canonical Wnt signaling in most developing systems, but rather function as quantitative transducers, or modulators, of Wnt signal intensity.

  • Source
    • "Pygo has also been implicated in Wnt-independent roles both in cancer [11] and in development [12] [13]. Human genome carries two orthologs of Drosophila Pygo, Pygo1 and Pygo2 [14]. Previous studies have provided evidence that the human Pygo is expressed in the majority of breast and epithelial ovarian primary carcinomas [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human Pygopus 2 (Pygo2) was recently discovered to be a component of the Wnt signaling pathway required for β-catenin/Tcf-mediated transcription. But the role of Pygo2 in malignant cell proliferation and invasion has not yet been determined.
    Preview · Article · Jul 2015
  • Source
    • "Pygo1 knockout mice are viable and fertile, with no apparent phenotype. Compound Pygo1/Pygo2 knockout mutants are indistinguishable from Pygo2 knockout, suggesting that Pygo2 plays the more important role during development (Li et al. 2007; Schwab et al. 2007; M Aguet, unpubl.). Unlike in Drosophila, in mice, Pygo1 and Pygo2 are now considered to be tissue-specific Wnt pathway components. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bcl9 and Bcl9l (Bcl9/9l) encode Wnt signaling components that mediate the interaction between β-catenin and Pygopus (Pygo) via two evolutionarily conserved domains, HD1 and HD2, respectively. We generated mouse strains lacking these domains to probe the β-catenin-dependent and β-catenin-independent roles of Bcl9/9l and Pygo during mouse development. While lens development is critically dependent on the presence of the HD1 domain, it is not affected by the lack of the HD2 domain, indicating that Bcl9/9l act in this context in a β-catenin-independent manner. Furthermore, we uncover a new regulatory circuit in which Pax6, the master regulator of eye development, directly activates Bcl9/9l transcription.
    Full-text · Article · Sep 2014 · Genes & Development
  • Source
    • ", 2009 ; Li et al . , 2007 ; Schwab et al. , 2007 ; Song et al. , 2007 ) and in human colorectal cancer cells with activated b - catenin ( Adachi et al. , 2004 ; Brembeck et al. , 2004 ; de la Roche fingers are enhanced by their binding to HD1 , ascribing a cofactor role to BCL9 / B9L in promoting Pygo ' s histone binding. The underlying mechanism is an allosteric communication , trig - gered by HD1 binding to PHD and relayed to its histone - binding surface through the PHD core ( Miller et al. , 2010 ). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pygo proteins promote Armadillo- and β-catenin-dependent transcription, by relieving Groucho-dependent repression of Wnt targets. Their PHD fingers bind histone H3 tail methylated at lysine 4, and to the HD1 domain of their Legless/BCL9 cofactors, linking Pygo to Armadillo/β-catenin. Intriguingly, fly Pygo orthologs exhibit a tryptophan > phenylalanine substitution in their histone pocket-divider which reduces their affinity for histones. Here, we use X-ray crystallography and NMR, to discover a conspicuous groove bordering this phenylalanine in the Drosophila PHD-HD1 complex-a semi-aromatic cage recognizing asymmetrically methylated arginine 2 (R2me2a), a chromatin mark of silenced genes. Our structural model of the ternary complex reveals a distinct mode of dimethylarginine recognition, involving a polar interaction between R2me2a and its groove, the structural integrity of which is crucial for normal tissue patterning. Notably, humanized fly Pygo derepresses Notch targets, implying an inherent Notch-related function of classical Pygo orthologs, disabled in fly Pygo, which thus appears dedicated to Wnt signaling.
    Full-text · Article · Oct 2013 · Structure
Show more