GATA4 transcription factor is required for ventral morphogenesis and heart tube formation.

Abstract

Previous studies have suggested that the GATA4 transcription factor plays an important role in regulating mammalian cardiac development. In the studies described in this report we have used gene targeting to produce GATA4-deficient mice. Homozygous GATA4-deficient (GATA4-/-) mice died between 8.5 and 10.5 days post coitum (dpc). GATA4-/- embryos displayed severe defects in both rostral-to-caudal and lateral-to-ventral folding, which were reflected in a generalized disruption of the ventral body pattern. This resulted in the defective formation of an organized foregut and anterior intestinal pore, the failure to close both the amniotic cavity and yolk sac, and the uniform lack of a ventral pericardial cavity and heart tube. Analysis of cardiac development in the GATA4-/- mice demonstrated that these embryos developed splanchnic mesoderm, which differentiated into primitive cardiac myocytes that expressed contractile proteins. However, consistent with the observed defect in ventral morphogenesis, these GATA4-/- procardiomyocytes failed to migrate to the ventral midline to form a linear heart tube and instead formed aberrant cardiac structures in the anterior and dorsolateral regions of the embryo. The defect in ventral migration of the GATA4-/- procardiomyocytes was not cell intrinsic because GATA4-/- cardiac myocytes and endocardial cells populated the hearts of GATA4-/- -C57BL/6 chimeric mice. Taken together, these results demonstrated that GATA4 is not essential for the specification of the cardiac cell lineages. However, they define a critical role for GATA4 in regulating the rostral-to-caudal and lateral-to-ventral folding of the embryo that is needed for normal cardiac morphogenesis.

Cardiac patterning and morphogenesis in zebrafish

“…Furthermore, promoter analysis in transgenic mice and frogs has demonstrated that Gata factor consensus sites are required for the regulation of nkx2.5 expression (Searcy et al, 1998;Lien et al, 1999;Reecy et al, 1999;Sparrow et al, 2000). Even so, mice lacking any one of the gata4, gata5, or gata6 genes do not exhibit significant defects in cardiac patterning (Kuo et al, 1997;Molkentin et al, 1997Molkentin et al, , 2000Morrisey et al, 1998;Koutsourakis et al, 1999), suggesting some functional redundancy between Gata factors. Overall, these data strongly suggest conservation of Gata factor function during cardiac patterning in species ranging from insects to mammals.…”

“…As in zebrafish, mouse mutants with severe endodermal deficiencies exhibit cardiac fusion defects. For example, mice lacking gata4 have dramatic reductions of endodermal tissue as well as cardiac fusion defects (Kuo et al, 1997;Molkentin et al, 1997). Furthermore, cardiac fusion can be rescued in gata4 mutant mice by reconstituting the endoderm (Narita et al, 1997).…”

Different requirements for GATA factors in cardiogenesis are mediated by non‐canonical Wnt signaling

“…In mouse, loss of either GATA4 or GATA6 results in developmental arrest due to a requirement for these factors in the extraembryonic endoderm (Kuo et al, 1997;Koutsourakis et al, 1999). Studies using chimeras to circumvent this problem suggested that GATA4 has no evident function in cardiogenesis (Narita et al, 1997a) and that GATA6 is not required for specification of the myocardium (Kuo et al, 1997;Molkentin et al, 1997;Morrisey et al, 1998;Koutsourakis et al, 1999). In contrast, lossof-function studies in zebrafish and Xenopus show that GATA6 is required for the maintenance and differentiation of cardiac progenitors (Peterkin et al, 2003).…”

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

“…Gata4 and Gata6 knock-out mice are embryonic lethal at E8.5-9.5 and E6.5-7.5, respectively, whereas Gata5 knock-out mice are viable. The embryonic lethality arises because of the defects in cardiogenesis and visceral endoderm formation, respectively (Kuo et al, 1997;Morrisey et al, 1998). Although originally thought to be selectively expressed in the heart and gastrointestinal tract, from these knock-out mouse data, the GATA-4-5-6 subfamily is now being identified in several other organ systems and disease states, including the central nervous system (CNS), where it is poorly characterized.…”