Menu

Close

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 https://www.biorxiv.org/content/early/2018/01/17/249680

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

Background

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 *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

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

    Register here

    Also in the developmental biology category:

    Lineage tracing on transcriptional landscapes links state to fate during differentiation

    Caleb Weinreb, Alejo E Rodriguez-Fraticelli, Fernando D Camargo, et al.



    Selected by Yen-Chung Chen

    1

    Distinct ROPGEFs successively drive polarization and outgrowth of root hairs

    Philipp Denninger, Anna Reichelt, Vanessa Aphaia Fiona Schmidt, et al.



    Selected by Marc Somssich

    A direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

    Christopher M Uyehara, Daniel J McKay



    Selected by Natalie Dye

    A metabolic switch from OXPHOS to glycolysis is essential for cardiomyocyte proliferation in the regenerating heart

    Hessel Honkoop, Dennis de Bakker, Alla Aharonov, et al.



    Selected by Andreas van Impel

    1

    Reconstruction of the global neural crest gene regulatory network in vivo

    Ruth M Williams, Ivan Candido-Ferreira, Emmanouela Repapi, et al.



    Selected by Hannah Brunsdon

    Functional characterization of Arabidopsis ARGONAUTE 3 in reproductive tissue

    Pauline E Jullien, Stefan Grob, Antonin Marchais, et al.



    Selected by Chandra Shekhar Misra

    1

    Single cell RNA-Seq reveals distinct stem cell populations that drive sensory hair cell regeneration in response to loss of Fgf and Notch signaling

    Mark E. Lush, Daniel C. Diaz, Nina Koenecke, et al.

    AND

    Distinct progenitor populations mediate regeneration in the zebrafish lateral line.

    Eric D Thomas, David Raible



    Selected by Rudra Nayan Das

    1

    Force inference predicts local and tissue-scale stress patterns in epithelia

    Weiyuan Kong, Olivier Loison, Pruthvi Chavadimane Shivakumar, et al.



    Selected by Sundar Naganathan

    Embryo geometry drives formation of robust signaling gradients through receptor localization

    Zhechun Zhang, Steven Zwick, Ethan Loew, et al.



    Selected by Diana Pinheiro

    Unlimited genetic switches for cell-type specific manipulation

    Jorge Garcia-Marques, Ching-Po Yang, Isabel Espinosa-Medina, et al.



    Selected by Rafael Almeida

    1

    Applications, Promises, and Pitfalls of Deep Learning for Fluorescence Image Reconstruction

    Chinmay Belthangady , Loic A. Royer



    Selected by Romain F. Laine

    Maintenance of spatial gene expression by Polycomb-mediated repression after formation of a vertebrate body plan

    Julien Rougot, Naomi D Chrispijn, Marco Aben, et al.



    Selected by Yen-Chung Chen

    1

    The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility

    Yiqin Ma, Daniel J McKay, Laura Buttitta



    Selected by Gabriel Aughey

    1

    Embryo geometry drives formation of robust signaling gradients through receptor localization

    Zhechun Zhang, Steven Zwick, Ethan Loew, et al.



    Selected by Paul Gerald L. Sanchez and Stefano Vianello

    1

    Symmetry breaking in the embryonic skin triggers a directional and sequential front of competence during plumage patterning

    Richard Bailleul, Carole Desmarquet-Trin Dinh, Magdalena Hidalgo, et al.



    Selected by Alexa Sadier

    A SOSEKI-based coordinate system interprets global polarity cues in Arabidopsis

    Saiko Yoshida, Alja van der Schuren, Maritza van Dop, et al.



    Selected by Martin Balcerowicz

    1

    Also in the genetics category:

    Distinct ROPGEFs successively drive polarization and outgrowth of root hairs

    Philipp Denninger, Anna Reichelt, Vanessa Aphaia Fiona Schmidt, et al.



    Selected by Marc Somssich

    A direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

    Christopher M Uyehara, Daniel J McKay



    Selected by Natalie Dye

    MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

    Emily Yun-Chia Chang, James P Wells, Shu-Huei Tsai, et al.



    Selected by Katie Weiner

    1

    Super-resolution Molecular Map of Basal Foot Reveals Novel Cilium in Airway Multiciliated Cells

    Quynh Nguyen, Zhen Liu, Rashmi Nanjundappa, et al.



    Selected by Robert Mahen

    Single cell RNA-Seq reveals distinct stem cell populations that drive sensory hair cell regeneration in response to loss of Fgf and Notch signaling

    Mark E. Lush, Daniel C. Diaz, Nina Koenecke, et al.

    AND

    Distinct progenitor populations mediate regeneration in the zebrafish lateral line.

    Eric D Thomas, David Raible



    Selected by Rudra Nayan Das

    1

    The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility

    Yiqin Ma, Daniel J McKay, Laura Buttitta



    Selected by Gabriel Aughey

    1

    Ribosomal DNA and the rDNA-binding protein Indra mediate non-random sister chromatid segregation in Drosophila male germline stem cells

    George Watase, Yukiko Yamashita



    Selected by Maiko Kitaoka

    A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy.

    Joseph R Daniele, Ryo Higuchi-Sanabria, Vidhya Ramachandran, et al.



    Selected by Sandra Malmgren Hill

    Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

    Rodrigo R.R. Duarte, Nathaniel D. Bachtel, Marie-Caroline Cotel, et al.



    Selected by Joanna Cross

    The Toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner

    Federico Germani, Daniel Hain, Denise Sternlicht, et al.



    Selected by Rohan Khadilkar

    Rapid embryonic cell cycles defer the establishment of heterochromatin by Eggless/SetDB1 in Drosophila

    Charles A Seller, Chun-Yi Cho, Patrick H O'Farrell



    Selected by Gabriel Aughey

    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

    1

    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
    Close