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

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:

    Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of cell division, differentiation, and loss

    Judy Martin, Erin Nicole Sanders, Paola Moreno-Roman, et al.

    Selected by Natalie Dye

    From spiral cleavage to bilateral symmetry: The developmental cell lineage of the annelid brain

    Pavel Vopalensky, Maria Antonietta Tosches, Kaia Achim, et al.

    Selected by Erik Clark

    A 3D model of human skeletal muscle innervated with stem cell-derived motor neurons enables epsilon-subunit targeted myasthenic syndrome studies

    Mohsen Afshar Bakooshli, Ethan S Lippmann, Ben Mulcahy, et al.

    Selected by Chris Demers

    Lineage tracing axial progenitors using Nkx1.2CreERT2 mice defines their trunk and tail contributions

    Aida Rodrigo Albors, Pamela A Halley, Kate G Storey

    Selected by Pierre Osteil

    Feedback control of neurogenesis by tissue packing

    Tom W. Hiscock, Joel B. Miesfeld, Kishore R. Mosaliganti, et al.

    Selected by Sarah Morson


    Focal adhesion kinase regulates early steps of myofibrillogenesis in cardiomyocytes

    Nilay Taneja, Abigail C Neininger, Matthew R Bersi, et al.

    Selected by Vassilis Papalazarou

    Content-Aware Image Restoration: Pushing the Limits of Fluorescence Microscopy

    Martin Weigert, Uwe Schmidt, Tobias Boothe, et al.

    Selected by Uri Manor

    In vivo topology converts competition for cell-matrix adhesion into directional migration

    Fernanda Bajanca, Nadege Gouignard, Charlotte Colle, et al.

    Selected by Helen Zenner

    The expa1-1 mutant reveals a new biophysical lateral root organogenesis checkpoint

    Priya Ramakrishna, Graham A. Rance, Lam D. Vu, et al.

    Selected by Annika Weimer


    F-actin patches nucleated on chromosomes coordinate capture by microtubules in oocyte meiosis

    Mariia Burdyniuk, Andrea Callegari, Masashi Mori, et al.

    Selected by Binyam Mogessie

    Polarization of Myosin II refines tissue material properties to buffer mechanical stress.

    Maria Duda, Nargess Khalilgharibi, Nicolas Carpi, et al.

    Selected by Yara E. Sánchez Corrales

    Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth

    Alberto Rosello-Diez, Linda Madisen, Sebastien Bastide, et al.

    Selected by Natalie Dye

    An Epiblast Stem Cell derived multipotent progenitor population for axial extension

    Shlomit Edri, Penelope Hayward, Peter Baillie-Johnson, et al.

    Selected by Pierre Osteil


    The Trithorax group protein dMLL3/4 instructs the assembly of the zygotic genome at fertilization

    Pedro Prudêncio, Leonardo G. Guilgur, João Sobral, et al.

    Selected by Carmen Adriaens

    Observing the Cell in Its Native State: Imaging Subcellular Dynamics in Multicellular Organisms

    Tsung-li Liu, Srigokul Upadhyayula, Daniel E Milkie, et al.

    Selected by Arnaud Monnard, Gautam Dey

    Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth

    Alberto Rosello-Diez, Linda Madisen, Sebastien Bastide, et al.

    Selected by Anna Kicheva

    We want to make our website, and the services we provide, useful and reliable. This sometimes involves placing small amounts of information called cookies on the device you used to access the internet. If you continue to use this website we will assume you are happy to accept our cookies.