Heart Development

During embryonic development of the heart, Neuregulin-1 is expressed in endocardial cells, whereas its specific receptors, ErbB2 and ErbB4 are expressed by the adjacent myocardium, suggesting a paracrine signaling mechanism (Gassmann et al. 1995; Meyer and Birchmeier 1995). First evidence for a critical function of the Neuregulin-1/ErbB signaling system during heart development came from the analysis of Neuregulin-1, ErbB2, and ErbB4 null-mutant mice. These mice show corresponding defects in heart development, characterized by a lack of trabecu-lation, abnormally thinned myocardium, and enlarged heart cavities. As a consequence, homozygous mutant embryos die at midgestation, before E11 (Gassmann et al. 1995; Lee et al. 1995; Meyer and Birchmeier 1995; Kramer et al. 1996; Erick-son et al. 1997; Britsch et al. 1998; Liu et al. 1998). Elegant genetic approaches by several independent groups have unambiguously proven the essential function of Neuregulin-1 signals during embryonic heart development: in mice with a null mutation of the ErbB2 gene, a heart-specific function of ErbB2 was reconstituted by transgenic expression of an ErbB2 cDNA under the transcriptional control of heart-specific promoters (Nkx2.5, «-myosin heavy chain promoter). In such animals with a heart-specific rescue of ErbB2 function cardiac development was normalized. Moreover, mutant mice with rescued heart development survived to birth, indicating that early embryonic lethality observed in null mutants is due to cardiac dysfunction (Morris et al. 1999; Woldeyesus et al. 1999). Several other mutations associated with similar defects in heart development have been described, for example, of the ShcA gene, which encodes an adaptor protein that transmits signals provided by ErbB and other tyrosine kinase receptors (Lai and Pawson 2000). Interestingly, a G-protein-coupled serotonin receptor (5HT-2B) is required for normal heart development as well. The mutation of the corresponding gene is embryonic lethal. Mutant animals lack trabeculae and have reduced ErbB2 levels in their myocardium (Nebigil et al. 2000). These data suggest a crosstalk between two discrete signaling pathways, and transactivation of ErbB receptors by G-protein-coupled receptors has been previously demonstrated for the EGF receptor (Daub et al. 1996). It is important to note that the demonstration of identical cardiac phenotypes in Neuregulin-1, ErbB2, and ErbB4 mutant mice has provided compelling genetic evidence that Neuregulin-1 signals are specifically transduced by ErbB2/ErbB4 receptor heterodimers in the heart. Accordingly, myocardial development, i.e., trabeculation, appears normal in ErbB3 mutant mice, since ErbB3 has not been reported to be expressed by the myocardium (Erickson et al. 1997; Riethmacher et al. 1997). However, additional studies have suggested functions of ErbB3 in the development of the heart valve mesenchyme and the heart cushions (Erickson et al. 1997; Camenisch et al. 2002).

Little is known about the molecular mechanisms underlying the process of trabeculation as well as the mechanisms by which Neuregulin-1 signals control this process. Trabeculation has been considered as a morphogenetic response of the myocardium (Lemke 1996). Mutation of a cardiac voltage-dependent sodium channel, SCN5a/Nav1.5 also results in defective trabecule formation. SCN5a/Nav1.5 has been implicated in excitation-contraction coupling. Thus, trabeculation may be also regulated by the physiological properties of the developing myocardium (Papadatos et al. 2002). Data from in vitro studies concerning cellular responses of cardiomyocytes to Neuregulin-1 signals are controversial (Garratt et al. 2003). However, some studies suggest Neuregulin-1 to be involved in the control of proliferation and survival of cardiomyocytes (Zhao et al. 1998; Baliga et al. 1999).

ErbB2 null-mutant mice with heart-specific reconstitution of ErbB2 function die immediately after birth, due to multiple developmental defects in the peripheral nervous system. Conditional mutation of the ErbB2 gene using the Cre-loxP system (Lewandoski 2001; Britsch 2006) has allowed the assessment of postnatal cardiac functions of the Neuregulin-1/ErbB pathway. Intriguingly, mice with heart-specific ablation of the ErbB2 gene survive into adulthood, but develop clinical and pathological features of a dilated cardiomyopathy with reduced contractility, secondary myofiber hypertrophy, thinned ventricular walls, and enlarged ventricular cavities (Crone et al. 2002; Ozcelik et al. 2002). It is currently unclear by which mechanism Neuregulin-1/ErbB signals maintain functional integrity of the adult heart. However, ErbB2 and ErbB4 expression has been detected in the T-tubule system where they could interact with components of the excitation-contraction coupling machinery (Ozcelik et al. 2002; Garratt et al. 2003; Ueda et al. 2005).

Because of potential clinical implications, the Neuregulin-1/ErbB signaling pathway in adult heart function has received great attention. This was very much accelerated by the clinical observation that treatment of breast cancer patients with a monoclonal antibody which specifically recognizes the human ErbB2/HER2 receptor (Trastuzumab, Herceptin) is accompanied by severe cardiotoxic side-effects, drawing a direct in vivo link from suppressed ErbB2 receptor signaling to impaired cardiac function (Slamon et al. 2001; Yarden and Sliwkowski 2001; Seidman et al. 2002). The role of ErbB2 mutants as models for cardiac diseases will be discussed in more detail in Sect. 2.4.1.

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