The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a vestige of embryonic development. 1,2 The function of these trabeculae in adults and their genetic architecture are unknown. To investigate this we performed a genome-wide association study using fractal analysis of trabecular morphology as an image-derived phenotype in 18,096 UK Biobank participants. We identified 16 significant loci containing genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborisation. 3,4 Using biomechanical simulations and human observational data, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomisation, we find a causal relationship between trabecular morphology and cardiovascular disease risk. These findings suggest an unexpected role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity, and reveal their influence on susceptibility to disease. MainThe chambers of the mature human heart have a complex inner surface whose function is unknown. Unlike the smooth endothelium of the great vessels, the endocardial surfaces of both ventricles are lined by a fenestrated network of muscular trabeculae which extend into the cavity. Their embryological development is driven by highly-conserved signalling pathways involving the endocardium-myocardium and extra-cellular matrix that regulate myocardial proliferation during cardiac morphogenesis. 2,[5][6][7][8][9] 1 Cell lineage tracing suggests that trabeculae have a molecular and developmental identity which is distinct from the compact myocardium. 10 The high surface area of trabeculae enables nutrient and oxygen diffusion from blood pool to myocardium before the coronary circulation is established. 1 Trabeculae are also vital to formation of the conduction system. 11 Theoretical analyses have proposed that their complex structure may contribute to efficient intra-ventricular flow patterns. 12-14 While hypertrabeculation is observed as a feature of some genetically-characterised cardiomyopathies, 15 the physiological function of trabeculae in adult hearts, their genetic architecture, and potential role in common disease have not been determined.The distinguishing trait of trabeculae is their branching morphology and the degree of such biological complexity in the heart can be quantified by fractal dimension (FD) analysis of cardiac magnetic resonance (CMR) imaging. 8 In a replicated genomewide association study (GWAS), using FD as an image-derived phenotype, we identify loci linked with trabecular morphology. Knockout models of loci-associated genes showed a marked decrease in trabecular complexity. Using biomechanical modelling and human observational data, we find a causal relationship between myocardial trabeculation and ventricular performance, with Mendelian randomisation showing that reduced trabecula...

We present Biomedisa, a free and easy-to-use open-source online platform developed for semi-automatic segmentation of large volumetric images. The segmentation is based on a smart interpolation of sparsely pre-segmented slices taking into account the complete underlying image data. Biomedisa is particularly valuable when little a priori knowledge is available, e.g. for the dense annotation of the training data for a deep neural network. The platform is accessible through a web browser and requires no complex and tedious configuration of software and model parameters, thus addressing the needs of scientists without substantial computational expertise. We demonstrate that Biomedisa can drastically reduce both the time and human effort required to segment large images. It achieves a significant improvement over the conventional approach of densely pre-segmented slices with subsequent morphological interpolation as well as compared to segmentation tools that also consider the underlying image data. Biomedisa can be used for different 3D imaging modalities and various biomedical applications.

The optic fissure is a transient gap in the developing vertebrate eye, which must be closed as development proceeds. A persisting optic fissure, coloboma, is a major cause for blindness in children. Although many genes have been linked to coloboma, the process of optic fissure fusion is still little appreciated, especially on a molecular level. We identified a coloboma in mice with a targeted inactivation of transforming growth factor β2 (TGFβ2). Notably, here the optic fissure margins must have touched, however failed to fuse. Transcriptomic analyses indicated an effect on remodelling of the extracellular matrix (ECM) as an underlying mechanism. TGFβ signalling is well known for its effect on ECM remodelling, but it is at the same time often inhibited by bone morphogenetic protein (BMP) signalling. Notably, we also identified two BMP antagonists among the downregulated genes. For further functional analyses we made use of zebrafish, in which we found TGFβ ligands expressed in the developing eye, and the ligand binding receptor in the optic fissure margins where we also found active TGFβ signalling and, notably, also gremlin 2b (grem2b) and follistatin a (fsta), homologues of the regulated BMP antagonists. We hypothesized that TGFβ is locally inducing expression of BMP antagonists within the margins to relieve the inhibition from its regulatory capacity regarding ECM remodelling. We tested our hypothesis and found that induced BMP expression is sufficient to inhibit optic fissure fusion, resulting in coloboma. Our findings can likely be applied also to other fusion processes, especially when TGFβ signalling or BMP antagonism is involved, as in fusion processes during orofacial development.

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Xmrk encodes a putative transmembrane glycoprotein of the tyrosine kinase family and is a melanoma‐inducing gene in Xiphophorus. We attempted to investigate the biological function of the putative Xmrk receptor by characterizing its signalling properties. Since a potential ligand for Xmrk has not yet been identified, it has been difficult to analyse the biochemical properties and biological function of this cell surface protein. In an approach towards such analyses, the Xmrk extracellular domain was replaced by the closely related ligand‐binding domain sequences of the human epidermal growth factor receptor (HER) and the ligand‐induced activity of the chimeric HER‐Xmrk protein was examined. We show that the Xmrk protein is a functional receptor tyrosine kinase, is highly active in malignant melanoma and displays a constitutive autophosphorylation activity possibly due to an activating mutation in its extracellular or transmembrane domain. In the focus formation assay the HER‐Xmrk chimera is a potent transforming protein equivalent to other tyrosine kinase oncoproteins.