Elevated WNT signalling disrupts heart development and may underlie some cases of human heterotaxy

Diamand KEM, Barratt KS, Alzahrani AS, Walsh K, Ahmed JN and Arkell RM

John Curtin School of Medical Research, The Australian National Univeristy, Canberra, ACT, 2601, Australia.

Congenital heart disease (CHD) is the most common type of birth defect and can occur in isolation or as part of a syndrome such as Heterotaxy, in which the laterality of internal organs is disrupted. Many cardiovascular abnormalities are associated with low heritability, hindering investigations into the genetic causes of CHD. Heterotaxy is the most highly heritable cardiovascular abnormality and is frequently shown to arise from mutation of the ciliome. Mutation of the X-linked transcription factor ZIC3 is associated with both isolated CHD and Heterotaxy but the cellular and molecular cause of ZIC3-associated Heterotaxy remains unknown. A genetic screen for mutations that affect murine embryogenesis identified a novel null allele of Zic3, called katun (Ka). The mutant embryos exhibit Heterotaxy and also incompletely penetrant, partial (posterior) axis duplications and anterior truncation. These latter two phenotypes are redolent of elevated canonical Wnt signalling. ZIC3 is a member of the Zic family of transcriptional regulators and previous work has shown that the ZICs can interact with TCF proteins to inhibit Wnt/β-catenin mediated transcription when overexpressed in cell lines. This raises the possibility that dysregulated WNT signalling may underlie some cases of Heterotaxy and CHD. We have investigated this notion using mouse genetics and find that ZIC3 loss-of-function leads to elevated WNT signalling, that elevated WNT signalling is consistently associated with heart defects and Heterotaxy during embryogenesis in the absence of pronounced cilia defects. Precisely how elevated WNT signalling interferes with the laterality of internal organs is being investigated.