The role ofthe transcription factor GATA-6 in mouse embryonic development
(De rol van de transcriptie factor GATA-6 tijdens de embryonale ontwikkeling van de muis)
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Different members of the GAT A family of transcription factors have been studied extensively in our lab. The role of GAT A-I in the differentiation of erythroid blood cells and of GATA-3 during T-lymphocyte development are two typical examples. GATA-6 is the most recently characterized member of the family. Based on its expression pattern during mouse embryonic developmentfor a role for GATA-6 in cardiogenesis had been speculated. To investigate what role GATA-6 may play during embryogenesis we used targeted inactivation of the gene in Embryonic Stem (ES) cells (chapter 2). Unexpectedly, homozygote mutant embryos die just after implantation at embryonic day 5.5. Generation of chimeric embryos in which the GATA-6 mutant cell population was confmed in either the embryo or to the extraembryonic tissues revealed that the primary defect in GATA-6 null embryos lies in an extraembryonic cell lineage. Further in vivo and in vitro analysis of the mutant embryos suggested that the affected lineage is the visceral yolk sac endoderm, a derivative of the primitive endoderm. Cardiogenesis could not be directly studied since mutant embryos die well before heart development starts (embryonic day 8.5). However, in chimeric embryos, GATA-6 -/- ES cells give rise to cardiomyocytes in apparently normal hearts, possibly due to redundant functions with the coexpressed GATA-4 and -5. In contrast, GATA-6 is the only member of the family that is expressed in the lung endoderm. Following on a published observation showing no contribution of GATA-6 null ES cells to the lung epithelium, we decided to generate more highly chimeric embryos to analyze the development of the lung, which is a derivative of another endoderm lineage, the definitive endoderm (chapter 3). Surprisingly, we found that lung endoderm can be formed from GATA-6 mutant cells. However, this mutant endoderm has subsequent morphogenetic and differentiation defects. The importance of GATA-6 protein levels during lung development was confirmed by a different approach. The gene was overexpressed in transgenic mice with a pulmonary epithelium specific promoter (chapter 4). High levels of the protein resulted in branching defects and more interestingly in a block oflung endoderm differentiation to distal alveolar epithelium.
- gata 6
- gata -6
- chimeric embryos