Alteration of Differentiation Potentials by Modulating GATA Transcription Factors in Murine Embryonic Stem Cells

Abstract

Background. Mouse embryonic stem (ES) cells can be differentiated in vitro by aggregation and/or retinoic acid (RA) treatment. The principal differentiation lineage in vitro is extraembryonic primitive endoderm. Dab2, Laminin, GATA4, GATA5, and GATA6 are expressed in embryonic primitive endoderm and play critical roles in its lineage commitment. Results. We found that in the absence of GATA4 or GATA5, RA-induced primitive endoderm differentiation of ES cells was reduced. GATA4 (−/−) ES cells express higher level of GATA5, GATA6, and hepatocyte nuclear factor 4 alpha marker of visceral endoderm lineage. GATA5 (−/−) ES cells express higher level of alpha fetoprotein marker of early liver development. GATA6 (−/−) ES cells express higher level of GATA5 as well as mesoderm and cardiomyocyte markers which are collagen III alpha-1 and tropomyosin1 alpha. Thus, deletion of GATA6 precluded endoderm differentiation but promoted mesoderm lineages. Conclusions. GATA4, GATA5, and GATA6 each convey a unique gene expression pattern and influences ES cell differentiation. We showed that ES cells can be directed to avoid differentiating into primitive endoderm and to adopt unique lineages in vitro by modulating GATA factors. The finding offers a potential approach to produce desirable cell types from ES cells, useful for regenerative cell therapy.

Retinoic Acid Signaling Plays a Restrictive Role in Zebrafish Primitive Myelopoiesis

“…In Xenopus embryos, excessive RA causes expanded expressions of GATA4/5/6 [45]. Consistent with its enhancing expressions of the GATA factors, RA commits mouse ES cells to differentiate into endoderm by enhancing expressions of GATA6 and GATA4 [42], [46], and directs urothelial specification of the ES cells by activating GATA4/6 signaling [43]. However, gata4 expression was significantly reduced or completely abolished respectively in zebrafish embryos at 8-somite stage that were treated with 100 nM RA or 300 nM RA at 40% epiboly for 1 h [34].…”

Epigenetic regulation of histone modifications and Gata6 gene expression induced by maternal diet in mouse embryoid bodies in a model of developmental programming

“…Whilst Emb-LPD EBs had downregulated Gata6 expression, Gata4 expression was not significantly affected. In ES cells, absence of Gata6 gene leads to loss of Gata4 expression whilst absence of Gata4 gene does not inhibit Gata6 expression, indicating a hierarchical relationship [ 21 , 32 , 33 ]. However, functional redundancy exists between Gata6 and Gata4 expression in other models including pancreatic and ovarian germ cell differentiation and in EBs during myocyte differentiation with Gata4 expression not dependent upon Gata6 expression [ 34 - 36 ].…”

“…The endocytic function in Emb-LPD EBs is stimulated together with increased expression of megalin as a compensatory response to maternal diet [ 11 ] and Dab2 expression and function is likely protected in the EB model to achieve this. Dab2 expression may be maintained either by a Gata4 -dependent pathway [ 33 , 38 ], by Gata6 being above the threshold required for Dab2 promoter activation or by an alternative mechanism. We anticipate that the growth stimulation coinciding with reduced expression of Gata6 but not Dab2 in Emb-LPD EBs will be partly driven by the increased nutrient delivery provided by enhanced endocytosis.…”

Deciphering the protein dynamics and molecular determinants of iPSC-derived neurons

“…Interestingly, the majority of the transcripts that were downregulated showed a relative high protein expression level, as for instance TPD52L1, AKR1C3 and DAB2. Recent data have shown that these proteins are regulators of cell differentiation [92][93][94]. The majority of these most upregulated transcripts were upregulated in proteomics data for both neuronal subtypes and, vice versa, the majority of these upregulated proteins were upregulated in transcriptomic data.…”