Ra And Heart Development

The significance of RA for embryonic and fetal heart development has been established in numerous studies (Clagett-Dame and DeLuca, 2002; Wilson and Warkany, 1950a; Wilson et a/., 1953; Zile, 2004). Embryonic exposure to either an excess or a deficiency of vitamin A leads to abnormal development, suggesting that the embryo requires a precisely regulated amount of RA. Evidence gathered from the study of retinoid-induced em-bryopathy and of RAR gene knockouts and mutations suggests multiple roles for RA in embryonic heart development.

1. Retinoic Acid-Mediated Signaling Is Required for Normal Heart Development

RA is critical in the development of the heart. It was recognized in the 1930s that maternal insufficiency of vitamin A, during pregnancy, results in fetal death and severe congenital malformations in the offspring, including aberrant heart development (Hale, 1937; Mason, 1935). The retinoid dependence of cardiogenesis was first shown in VAD rats, which displayed specific aortic arch and ventricular septal deficits (Wilson and Warkany, 1950a,b; Wilson et a/., 1953). RA function during embryonic and fetal heart development at the molecular level has been extensively studied, including the use of transgenic mice with mutations in retinoid receptor genes, or retinoid-ligand knockout models (Ghyselinck et a/., 1998; Kastner et a/., 1994; Luo et a/., 1996; Mic et a/., 2002; Niederreither et a/., 2001; Smith et a/., 1998). Using cultured embryonic stem cells or cardiomyocytes, it has been demonstrated that RA accelerates expression of cardiac-specific genes, enhances the development of ventricular cardiomyocytes, and promotes cardiomyocyte differentiation, indicating that RA-mediated signaling has an important role in embryonic cardiomyocyte proliferation and differentiation (Aranega et a/., 1999; Hidaka et a/., 2003; Honda et a/., 2005; Wobus et a/., 1997). Specific functions of the different retinoid receptors during heart embryogenesis have been identified over the past decade. Although the different receptor isoforms have unique distributions during development, knocking out one specific isoform of the RAR family does not cause developmental defects analogous to those observed in the fetal vitamin A deficiency syndrome, demonstrating a redundancy between members of each receptor subtype. Mice deficient for individual RARa1, RARß2, and RARg2 isoforms or all RARb isoforms appear normal (Li et a/., 1993; Lohnes et a/., 1993; Lufkin et a/., 1993; Luo et a/., 1995; Mendelsohn et a/., 1994b). Although RARa and RARg gene null mutants display early postnatal lethality or growth deficiency, the heart development is normal (Lohnes et a/., 1993; Lufkin et a/., 1993).

In contrast with RAR single mutants, compound null mutations of RAR genes lead to significant heart malformations (Lohnes et al., 1994; Mendelsohn et al., 1994a). A marked defect observed in the heart and outflow tract of double mutant fetuses was persistent truncus arteriosus. The truncus arteriosus is a transient structure, which by 14.5 dpc should be completely divided into the ascending aorta and pulmonary trunk, by the spiral-shaped aorticopulmonary septum (Fananapazir and Kaufman, 1988; Vuillemin and Pexieder, 1989). Failure of this division to take place or to become complete results in a persistent truncus arteriosus, receiving blood from both ventricles. In addition, ventricular septal defects, myocardial deficiency, persistent atrio-ventricular canal, and an abnormal aortic arch pattern were found in RAR double mutants (Lee et al., 1997; Luo et al., 1996; Mendelsohn et al., 1994a). All of these abnormalities have been described in the offspring from VAD rats (Wilson and Warkany, 1950a; Wilson et al., 1953) (Table I). These results demonstrate that RAR-mediated retinoid signaling is essential for proper myocardial growth, aorticopulmonary and ventricular septation, and patterning of the aortic arches.

RXRs exert multiple functions in several signaling systems (Mangelsdorf and Evans, 1995), and RAR/RXR heterodimers bind more efficiently to RAREs than homodimers of either RAR or RXR. Furthermore, RXRs enhance the binding of other nuclear receptors (Kastner et al., 1994; Leid et al., 1992). Thus, RXRs act as partners of multiple nuclear receptors and are pleiotropic in cellular effects. Disruption of the RXRa gene results in prominent cardiac defects, including hypoplasia of the ventricular compact zone and muscular ventricular septal defects. Embryonic heart failure was also displayed in the RXRa embryo (Dyson et al., 1995; Kastner et al., 1994; Sucov et al., 1994). Atrial and ventricular chamber-specific myosin light chain 2 (MLC-2) genes have been used as molecular markers for the process of chamber maturation and specification (Kubalak et al., 1994; O'Brien et al., 1993). The expression of the atrial isoform MLC-2a appears to be uniform throughout the linear heart tube and is selectively down-regulated in the ventricular chamber during the process of expansion of the compact zone and onset of trabeculation. An aberrant, persistent expression of MLC-2a in the thin-walled ventricular chambers was identified in the RXRa mutant, indicating that the RXRa-mediated pathway is important for differentiation of ventricular cardiomyocytes and is required in the progression of development of the ventricular region of the heart from its early atrial-like form to the thick-walled adult ventricle. The conduction system disturbances found in RXRa embryos indicate that an RXRa-mediated signaling pathway is required in the developing conduction system. Interestingly, RXRb and RXRg gene knockout mice develop normal heart formation. Moreover, double mutation of RXRb_/_/RXRgor triple mutation of RXRa+/ /RXRb ^/RXRg ^ phenotypes are viable, displaying no obvious congenital heart abnormalities except a marked growth

TABLE I. Cardiovascular Receptor Knockout Embryos

Defects in Vitamin A Deficiency

or Excess and Retinoid

Persistant Ventricular Atrial Abnormal Heart truncus Tubular septal septal aortic arch defects arteriosus heart defect defect pattern

Atrio-ventricular canal defect

Ventricular chamber hypoplasia

VAD + +

+ - +



Excess RA + +

+ + +


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