Cardiac Development and Ageing
Professor Thomas Brand, Head of Group
Professor Brand is interested in various aspects of cardiac development and ageing. In his group three different model systems i.e. mouse, zebrafish and chick embryos are employed. Current projects in the laboratory include:
Left-right axis development
The heart among many other internal organs is positioned on the left side of the body. Moreover many elements of the heart are asymmetric including the right-sided position of the caval veins and the sinus node. Also the myocardium of the inflow and outflow tract displays asymmetric morphology. Currently only the Nodal-Pitx2 pathway has been implicated in establishing cardiac asymmetry. While many aspects of asymmetric development in the heart are Pitx2-dependent, others such as cardiac looping are independent of this pathway, suggesting the existence of an independent pathway that govern certain aspects of heart development. We recently identified FGF8-Snai1 as novel determinants for the sidedness of proepicardial development, which in the chick embryo develops only on the right side (Fig. 1; Schlueter et al. 2009)
Fig. 1 (A) Detection of gene expression by in situ hybridization of Tbx18 (proepicardial marker gene, blue) and Pitx2 (left side marker gene, red) in the chick heart at HH stage 13 demonstrating asymmetric expression of both genes on the right and left side, respectively. (B) Depiction of a tubular heart of a chick embryo at HH stage 17. The proepicardium (blue vesicles) develops asymmetrically only on the right side.
Proepicardial development
The heart initially consists of only two cell layers, the myocardium and endocardium. The outer layer of the mature heart, the epicardium is subsequently added to the tubular heart and is derived from a structure, the proepicardium, which develops at the base of the venous inflow tract (Fig. 2). The proepicardium makes contact to the surface of the embryonic heart and the cells establish an epithelial layer, the primitive epicardium. Some cells migrate onto the ventricular wall and differentiate into the coronary arteries and cardiac fibroblasts. We are particularly interested in defining the molecular signals that govern proepicardium formation and thus far identified BMP2 (Schlueter et al. 2006) and FGF (Torlopp et al. 2010) as important signalling molecules regulating proepicardium formation These signals might also be important during cardiac regeneration. Particularly in the zebrafish it has been shown that the epicardium gets activated after cardiac wounding and this is essential for cardiac regeneration. We want to analyze the role of epicardial cell activation during zebrafish regeneration using various transgenic GFP-reporter lines.
Fig. 2 (A) Chick embryo at HH stage 17 displaying the proepicardium (PE) at the venous pole of the heart. (B) Depiction of the developmental processes involved in the generation of the different derivatives of the epicardium.
Functional analysis of the Popeye domain containing gene family
The Popeye domain containing (Popdc) gene family encode membrane proteins, which are predominantly expressed in heart and skeletal muscle, however other cell types such as some neurones and epithelial cells do also express Popeye genes. Null mutations of Popdc1 and Popdc2 have been engineered by introducing a LacZ reporter gene into the first coding exon. With the help of the LacZ reporter gene, expression during embryonic and postnatal life has been documented (Andrée et al., 2002 ; Froese and Brand, 2008 ) (Fig. 3). Both mutants were viable and did not reveal any severe congenital heart defect. However, both animals displayed a stress-induced bradycardia. This cardiac conduction disease develops in an age-dependent manner. The phenotype is reminiscent of sick sinus syndrome in humans, which also becomes particular abundant amongst the elderly. Likewise in zebrafish Popdc1 and Popdc2 morphants have been engineered and both animals revealed conduction abnormalities. Current work in the laboratory aims at defining the biochemical and cell biological basis of the cardiac conduction defect. Work also involves the electrophysiological analysis in isolated cardiac myocytes.
Fig. 3 Transgenic Popdc2-LacZ embryo at E11.5 displaying LacZ expression in the heart and visceral smooth muscle of the developing gut.
Selected Publications
Torlopp A; Schlueter J; Brand T. (2010). Role of fibroblast growth factor signaling during proepicardium formation in the chick embryo. Dev Dyn. 239:2393-403.
Schlueter J; Brand T. (2009). A right-sided pathway involving FGF8/Snai1 controls asymmetric development of the proepicardium in the chick embryo. Proc Natl Acad Sci U S A. 106:7485-7490.
Froese A; Brand T. (2008). Expression pattern of Popdc2 during mouse embryogenesis and in the adult. Dev Dyn. 237:780-787.
Schlueter J; Männer J; Brand T. (2006). BMP is an important regulator of proepicardial identity in the chick embryo. Dev Biol. 295:546-558.
Andree B; Fleige A; Arnold HH; Brand T. (2002). Mouse Pop1 is required for muscle regeneration in adult skeletal muscle. Mol Cell Biol. 22:1504-1512.
Professor Thomas Brand and members of his research group, June 2011
