Tissue specific requirements for WNT11 in developing outflow tract and dorsal mesenchymal protrusion

Abstract

Correct cardiac development is essential for fetal and adult life. Disruptions in a variety of signaling pathways result in congenital heart defects, including outflow and inflow tract defects. We previously found that WNT11 regulates outflow tract development. However, tissue specific requirements for WNT11 in this process remain unknown and whether WNT11 is required for inflow tract development has not been addressed. Here we find that germline Wnt11 null mice also show hypoplasia of the dorsal mesenchymal protrusion (DMP), which is required for atrioventricular septation. Ablation of Wnt11 with myocardial cTnTCre recapitulated outflow tract defects observed in germline Wnt11 null mice, but DMP development was unaffected. In contrast, ablation of Wnt11 with Isl1Cre fully recapitulated both outflow tract and DMP defects of Wnt11 germline nulls. DMP hypoplasia in Wnt11 mutants was associated with reduced proliferation within the DMP, but no evident defects in myocardial differentiation of the DMP. Examination of Pitx2-, Axin2-, or Patched-lacZ reporter mice revealed no alterations in reporter expression, suggesting that WNT11 was required downstream of, or in parallel to, these signaling pathways to regulate DMP formation. These studies revealed a previously unappreciated role for WNT11 for DMP formation and distinct tissue-specific requirements for WNT11 in outflow tract and DMP development.

Planar Cell Polarity Signaling in Mammalian Cardiac Morphogenesis

“…Prior mouse genetic studies have revealed that the PCP pathway is critical for OFT formation in mammals. Loss of the presumptive PCP ligands Wnt5a and Wnt11 results in OFT malformation primarily in the form of PTA [63], and DORV or TGA [64, 65], respectively. Similarly, mutations of core PCP genes, including Fz1, 2, 7; Dvl1, 2, 3 ; and Vangl2 cause various OFT defects ranging from DORV, TGA to PTA [37, 61, 66–69].…”

Planar cell polarity signaling regulates polarized second heart field morphogenesis to promote both arterial and venous pole septation

“…Although the defects in these mutants have all been attributed to OFT shortening, the cause of which varies. Analysis of Wnt11 and Vangl2 revealed that they are required within OFT myocardium for cell polarization and organization during OFT elongation (Ramsbottom et al, 2014;van Vliet et al, 2017). In contrast, we and others have found that Wnt5a is highly expressed in the caudal SpM-SHF but not the OFT (Chen et al, 2012;Li et al, 2016;Sinha et al, 2015aSinha et al, , 2012.…”

“…In mice, germline deletion of Wnt5a, which encodes a presumptive mammalian PCP ligand, leads to CAT with almost full penetrance, whereas disruption of other PCP genes, Wnt11, Dvl1/2/3 and Vangl2 (Vang like 2), causes a spectrum of OFT defects from DORV to CAT (Etheridge et al, 2008;Person et al, 2010;Ramsbottom et al, 2014;Sinha et al, 2012;van Vliet et al, 2017). Although the defects in these mutants have all been attributed to OFT shortening, the cause of which varies.…”

A deficiency in SUMOylation activity disrupts multiple pathways leading to neural tube and heart defects in Xenopus embryos

“…Disruption of the non-canonical Wnt pathway can also account for the cardiac and neural tube defects that occur later in embryo development. Wnt 11 and Fzd7 are required at multiple points during Xenopus heart development, not only early in the specification of cardiac progenitor cells, but also in cardiac morphogenesis (septation and outflow tract development) [56–61]. The ensuing decreased activity of Dishevelled (Dvl) in Gam1 embryos is fully consistent with the cardiac and neural tube phenotypes of Dvl-deficient mice and Xenopus [62–64].…”