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

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

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