Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling

Claudio Cantù, Anastasia Felker, Dario Zimmerli, Elena Chiavacci, Elena Maria Cabello, Lucia Kirchgeorg, Tomas Valenta, George Hausmann, Jorge Ripoll, Natalie Vilain, Michel Aguet, Konrad Basler, Christian Mosimann

Preprint posted on January 17, 2018

Nuclear regulators of the Wnt/ß-catenin pathway – previously associated with human developmental cardiac malformations - as key players during vertebrate heart patterning.

Selected by Andreas van Impel


Genetic alterations in BCL9 and BCL9-like have previously been associated with the development of congenital heart disease in humans, a condition that nearly affects 1% of the population and presents with various structural and functional abnormalities of the heart. BCL9 proteins and their interaction partners PYGO1/2 have been shown to act as co-factors of nuclear ß-catenin in the context of canonical Wnt signalling. Despite the involvement of the Wnt pathway in several aspects of cardiac development, a function for BCL9/PYGO genes during vertebrate heart formation has not been reported so far.


Key findings

Here, the authors of this preprint tackle the question whether BCL9 and PYGO are required for heart development, making use of two vertebrate model systems: zebrafish and mouse. In both species, loss of either protein function results in severe cardiac defects. Importantly, interference with the BCL9/PYGO complex seems to cause a selective reduction of canonical Wnt signalling levels in the heart and other affected tissues but does not systemically abrogate transcriptional activity of ß-catenin suggesting that both proteins are involved in mediating only a specific subset of Wnt signalling events in mouse and zebrafish embryos. Using conditional knock-outs in mice the authors further demonstrate a specific requirement for Bcl9/Pygo in early mesodermal cardiac progenitors and in migrating cardiac neural crest cells, two key lineages during heart development. Mechanistically, the ß-catenin/BCL9/PYGO complex seems to control the expression of a specific subgroup of Wnt target genes including key transcription factors that are essential for different steps during heart patterning.


Loss of functional BCL9 proteins in mice results in pronounced heart defects (thinned myocardium of the ventricular walls; malformations of the forming septum, the atrio-ventricular valves and the outflow tract) and a reduced expression of a Wnt reporter (BATgal) in the outflow tract. Reproduced from Cantu et al Fig 3c-f.


How I believe this moves the field forward

The preprint from Cantù and colleagues identifies BCL9 and PYGO as essential tissue-specific co-factors of ß-catenin that selectively mediate the activation of canonical Wnt target genes during vertebrate cardiac development. In my view this is a significant finding as the presented results strongly imply that the reported genomic alterations in BCL9 genes in humans with congenital heart disease are indeed causative or at least contribute to the respective cardiac malformations found in patients. Therefore, this study gives important new insights into the molecular basis of congenital heart disease in humans.


Open questions

  • How is the tissue-specific activity of BCL9/PYGO brought about and how is it regulated? Is the (overlapping) expression of both genes restricted to the affected tissues?
  • Is there a common set of cardiac target genes downstream of BCL9/PYGO/ß-catenin signalling in mice and zebrafish that might also be misregulated in human patients?
  • Is the cardiac function of BCL9/PYGO restricted to early developmental processes or is this complex also required at later stages, e.g. in response to cardiac injury?


Further reading – useful reviews

Grant, M. G., Patterson, V. L., Grimes, D. T., Burdine, R. D. (2017) Modeling Syndromic Congenital Heart Defects in Zebrafish. Curr Top Dev Biol.;124:1-40.

Andersen, T. A., Troelsen, K. de L. L. & Larsen, L. A. (2013) Of mice and men: molecular genetics of congenital heart disease. Cell Mol Life Sci 71, 1327–52.

Mosimann, C., Hausmann, G., Basler, K. (2009) Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nature Reviews. Molecular Cell Biology, 10(4):276-286.

Tags: cardiac development, disease model, mouse, wnt signalling, zebrafish

Posted on: 7th February 2018 , updated on: 21st February 2018

Read preprint (No Ratings Yet)

  • Have your say

    Your email address will not be published. Required fields are marked *

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the developmental biology category:

    A histidine kinase gene is required for large radius root tip circumnutation and surface exploration in rice

    Kevin R Lehner, Isaiah Taylor, Erin N McCaskey, et al.

    Selected by Martin Balcerowicz

    Actomyosin-driven tension at compartmental boundaries orients cell division independently of cell geometry in vivo

    Elena Scarpa, Cedric Finet, Guy Blanchard, et al.

    Selected by Ivana Viktorinová

    Molecular organization of integrin-based adhesion complexes in mouse Embryonic Stem Cells

    Shumin Xia, Evelyn K.F. Yim, Pakorn Kanchanawong


    Superresolution architecture of pluripotency guarding adhesions

    Aki Stubb, Camilo Guzmán, Elisa Närvä, et al.

    Selected by Nicola Stevenson, Amanda Haage

    Transcriptional initiation and mechanically driven self-propagation of a tissue contractile wave during axis elongation

    Anais Bailles, Claudio Collinet, Jean-Marc Philippe, et al.

    Selected by Sundar Naganathan


    Revealing the nanoscale morphology of the primary cilium using super-resolution fluorescence microscopy

    Joshua Yoon, Colin J. Comerci, Lucien E. Weiss, et al.

    Selected by Gautam Dey

    Signaling dynamics control cell fate in the early Drosophila embryo

    Heath E Johnson, Stanislav Y Shvartsman, Jared E Toettcher

    Selected by Yara E. Sánchez Corrales


    Three-dimensional tissue stiffness mapping in the mouse embryo supports durotaxis during early limb bud morphogenesis

    Min Zhu, Hirotaka Tao, Mohammad Samani, et al.

    Selected by Natalie Dye

    PUMILIO hyperactivity drives premature aging of Norad-deficient mice

    Florian Kopp, Mehmet Yalvac, Beibei Chen, et al.

    Selected by Carmen Adriaens

    Synergy with TGFβ ligands switches WNT pathway dynamics from transient to sustained during human pluripotent cell differentiation

    Joseph Massey, Yida Liu, Omar Alvarenga, et al.

    Selected by Pierre Osteil


    3D Tissue elongation via ECM stiffness-cued junctional remodeling

    Dong-Yuan Chen, Justin Crest, Sebastian J Streichan, et al.

    Selected by Sundar Naganathan

    EGFR signaling coordinates patterning with cell survival during Drosophila epidermal development

    Samuel Henry Crossman, Sebastian J Streichan, Jean-Paul Vincent

    Selected by Sarah Bowling


    Damage-induced reactive oxygen species enable zebrafish tail regeneration by repositioning of Hedgehog expressing cells.

    Henry Roehl, Montserrat Garcia Romero, Gareth McCathie, et al.

    Selected by Alberto Rosello-Diez

    Arterio-Venous Remodeling in the Zebrafish Trunk Is Controlled by Genetic Programming and Flow-Mediated Fine-Tuning

    Ilse Geudens, Baptiste Coxam, Silvanus Alt, et al.

    Selected by Andreas van Impel

    Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing

    Qingyun Li, Zuolin Cheng, Lu Zhou, et al.

    Selected by Zheng-Shan Chong

    Polyacrylamide Bead Sensors for in vivo Quantification of Cell-Scale Stress in Zebrafish Development

    Nicole Traeber, Klemens Uhlmann, Salvatore Girardo, et al.

    Selected by Jacky G. Goetz

    millepattes micropeptides are an ancient developmental switch required for embryonic patterning

    Suparna Ray, Miriam I Rosenberg, Hélène Chanut-Delalande, et al.

    Selected by Erik Clark

    Also in the genetics category:

    Evidence for an Integrated Gene Repression Mechanism based on mRNA Isoform Toggling in Human Cells

    Ina Hollerer, Juliet C Barker, Victoria Jorgensen, et al.

    Selected by Clarice Hong

    Signaling dynamics control cell fate in the early Drosophila embryo

    Heath E Johnson, Stanislav Y Shvartsman, Jared E Toettcher

    Selected by Yara E. Sánchez Corrales


    PUMILIO hyperactivity drives premature aging of Norad-deficient mice

    Florian Kopp, Mehmet Yalvac, Beibei Chen, et al.

    Selected by Carmen Adriaens

    Arterio-Venous Remodeling in the Zebrafish Trunk Is Controlled by Genetic Programming and Flow-Mediated Fine-Tuning

    Ilse Geudens, Baptiste Coxam, Silvanus Alt, et al.

    Selected by Andreas van Impel

    CRISPR/Cas9-mediated gene deletion of the ompA gene in an Enterobacter gut symbiont impairs biofilm formation and reduces gut colonization of Aedes aegypti mosquitoes

    Shivanand Hegde, Pornjarim Nilyanimit, Elena Kozlova, et al.

    Selected by Snehal Kadam

    Neural crest cells regulate optic cup morphogenesis by promoting extracellular matrix assembly

    Chase Dallas Bryan, Rebecca Lynne Pfeiffer, Bryan William Jones, et al.

    Selected by Ashrifia Adomako-Ankomah


    The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila

    Arya Zandvakili, Juli Uhl, Ian Campbell, et al.

    Selected by Clarice Hong


    Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages is necessary for functional spinal cord regeneration in zebrafish

    Themistoklis M. Tsarouchas, Daniel Wehner, Leonardo Cavone, et al.

    Selected by Shikha Nayar


    JNK-mediated spindle reorientation in stem cells promotes dysplasia in the aging intestine

    Daniel Hu, Heinrich Jasper

    Selected by Maiko Kitaoka

    Phenotypic landscape of schizophrenia-associated genes defines candidates and their shared functions

    Summer B. Thyme, Lindsey M. Pieper, Eric H. Li, et al.

    Selected by Daniel Grimes

    Super-Mendelian inheritance mediated by CRISPR/Cas9 in the female mouse germline

    Hannah A. Grunwald, Valentino M. Gantz, Gunnar Poplawski, et al.

    Selected by Rebekah Tillotson


    The Ly6/uPAR protein Bouncer is necessary and sufficient for species-specific fertilization

    Sarah Herberg, Krista R Gert, Alexander Schleiffer, et al.

    Selected by James Gagnon

    Functional testing of a human PBX3 variant in zebrafish reveals a potential modifier role in congenital heart defects

    Gist H. Farr III, Kimia Imani, Darren Pouv, et al.

    Selected by Hannah Brunsdon

    A robust method for transfection in choanoflagellates illuminates their cell biology and the ancestry of animal septins

    David Booth, Heather Middleton, Nicole King

    Selected by Maya Emmons-Bell

    SWI/SNF remains localized to chromatin in the presence of SCHLAP1

    Jesse R Raab, Keriayn N Smith, Camarie C Spear, et al.

    Selected by Carmen Adriaens


    Genetic compensation is triggered by mutant mRNA degradation

    Mohamed El-Brolosy, Andrea Rossi, Zacharias Kontarakis, et al.

    Selected by Andreas van Impel