Disease relevance of Zfpm1

• In particular, rescued FOG-1-/- mice die at embryonic day (E) 14.5 with cardiac defects that include double outlet right ventricle and a common atrioventricular valve [1].
• First, individuals with a GATA1 mutation that blocks the interaction between GATA-1 and its cofactor Friend of GATA-1 (FOG-1) suffer from dyserythropoietic anemia and thrombocytopenia [2].
• Injection of zebrafish embryos with a morpholino directed against fog1 resulted in embryos with a large pericardial effusion and an unlooped heart tube [3].

High impact information on Zfpm1

• This highly conserved valine is necessary for interaction of the amino-terminal zinc finger of GATA-1 with its essential cofactor, FOG-1 (for friend of GATA-1; refs 9-12) [4].
• GATA-1 upregulated critical MegE-related transcription factors such as FOG-1 and GATA-2 in lymphoid and GM progenitors, and their MegE development did not require "permissive" erythropoietin signals [5].
• We show that FOG-1 can repress GATA-3-dependent activation of the IL-5 promoter in T cells [6].
• Also, FOG-1 overexpression during primary activation of naive T cells inhibited Th2 development in CD4+ T cells [6].
• FOG-1 overexpression repressed development of Th2 cells from naive T cells, but did not reverse the phenotype of fully committed Th2 cells [6].

Biological context of Zfpm1

• Multiple aspects of hematopoiesis are controlled by the interaction of FOG-1 with the GATA-1/2/3 subfamily [1].
• Here we show that GATA-4 cooperates with a Friend-of-GATA (FOG) cofactor to direct gene expression in this segment of gut [7].
• Point mutations near the N-terminus of FOG-1 that abrogate NuRD binding block gene repression by FOG-1 [8].
• Our studies define a molecular context for transcriptional activation by GATA-1 and FOG-1, and may explain the occurrence of tandem GATA and Ets elements in the promoters of numerous megakaryocyte-expressed genes [9].
• In contrast to male GATA-1(KI) (GATA-1 is located on the X-chromosome) or GATA-2(KI/KI) mice, compound GATA-1(KI) GATA-2(KI/KI) mutant mice display complete megakaryopoietic failure, a phenocopy of FOG-1(-/-) mice [10].

Anatomical context of Zfpm1

• Neural crest cells migrate properly into FOG-1-/- hearts and mice with FOG-1 conditionally excised from neural crest derivatives fail to develop cardiac abnormalities [1].
• Immunohistochemical staining revealed that GATA-4 and FOG-1 are co-expressed in hindstomach epithelial cells from embryonic days (E) 11.5 to 18 [7].
• The transcription factor GATA-1 and its cofactor FOG-1 are essential for the normal development of erythroid cells and megakaryocytes [9].
• How the GATA-1-FOG-1 complex controls the expression of distinct sets of gene in megakaryocytes and erythroid cells is not understood [9].
• The expression levels of FOG-1, GATA-1, and beta-chain in each hematopoietic cell line were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting [11].

Physical interactions of Zfpm1

• FOG-1 has also been observed to interact with the corepressor molecule C-terminal binding protein (CtBP) through a peptide motif shared by all FOG family members [12].

Regulatory relationships of Zfpm1

• FOG-1 can stimulate or inhibit GATA-1 activity depending on cell and promoter context [9].
• Importantly, we find that distinct regions of FOG-1 differentially influence erythroid versus megakaryocyte maturation [13].

Other interactions of Zfpm1

• In contrast, conditional inactivation of FOG-1 in endothelial-derived tissues by means of Tie-2-expressed Cre recapitulates the rescue-knockout defects [1].
• The FOG proteins (FOG-1 and FOG-2) can act as either enhancers or repressors of GATA transcriptional activity, depending on the cell and promoter context [14].
• As such, we propose that FOG-1 may modulate the fate of a bipotential erythroid/megakaryocytic precursor cell [13].
• Interaction between FOG-1 and the corepressor C-terminal binding protein is dispensable for normal erythropoiesis in vivo [12].
• We identify endocardial cushion expression of the transcription factor Fog1, and we demonstrate active Wnt/beta-catenin signaling in developing endocardial cushions suggesting pathways that have not been previously appreciated to participate in cardiac valve formation [15].

Analytical, diagnostic and therapeutic context of Zfpm1

• Whole-mount in situ hybridization revealed fog1 expression in the heart, the hematopoietic system, and the brain, while fog2a and fog2b expression was restricted to the brain [3].

References