Wild-Type Endoderm Abrogates the Ventral Developmental Defects Associated with GATA-4 Deficiency in the Mouse

Abstract

GATA-4 knockout mice die by 9.5 days postcoitum and exhibit profound defects in ventral morphogenesis, including abnormal foregut formation and a failure of fusion of the bilateral myocardial primordia. During early mouse development, GATA-4 is expressed in cardiogenic splanchnic mesoderm and associated endoderm, suggesting that the presence of this transcription factor in one or both of these tissue types is essential for ventral development. To distinguish whether GATA-4 expression in mesoderm or endoderm accounts for the phenotype of the knockout mouse, we prepared chimeric mice by injecting Gata4-/- ES cells into 8-cell stage ROSA26(Gata4+/+) embryos. We identified a series of high percentage null chimeras (8-10 days postcoitum) in which Gata4+/+ cells were restricted to visceral yolk sac endoderm and small portions of the foregut/hindgut endoderm. Despite an absence of GATA-4 in all other cells of these embryos, there was normal development of the heart, foregut, and surrounding tissues. We conclude that expression of GATA-4 in endoderm rather than cardiogenic mesoderm is required for ventral morphogenesis.

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

“…Our data confirm the previously suggested cell non-autonomous functions of GATA4 and GATA6 during cardiogenesis (Narita et al, 1997b;Peterkin et al, 2003;Afouda et al, 2008). In our previous investigation, we proposed a regulatory pathway controlling cardiogenesis, integrating cardiogenic GATA transcription factors with canonical and non-canonical Wnt signaling (Afouda et al, 2008).…”

Stem cells and the formation of the myocardium in the vertebrate embryo

“…While targeted disruption of these individual genes (e.g., Nkx2.5, GATA4, MEF2a, MEF2c, Bop, etc.) in knockout mice dramatically affected structural development of the heart, it did not prevent the formation of myocardial tissue (Lyons et al, 1995;Lin et al, 1997;Narita et al, 1997;Gottlieb et al, 2002;Naya et al, 2002). Since a great amount of development occurs between the stages when the precardiac stem cells are localized at HH stage 3 and the first appearance of these cardiac-associated genes at HH stage 6, a fair conclusion would be that expression of these transcription factors defines an early myocardial phenotype and not that of a precardiac stem cell.…”

“…Nonetheless, these transcription factors serve as markers of the cardiac phenotype because their combined expression is unique to the myocardium. For example, GATA4 expression is exhibited by myocardial, endothelial, and endodermal cells, while MEF2c is exhibited by both cardiac and skeletal muscle (Edmondson et al, 1994;Laverriere et al, 1994;Narita et al, 1997). However, cardiac muscle is the only tissue that expresses both transcription factors.…”

Cardiac patterning and morphogenesis in zebrafish

“…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). Future studies will reveal whether additional requirements for cardiac fusion, such as Mil activity or the early functions of hand genes, also apply in other vertebrates.…”