Disease relevance of Zfpm2

• Our findings indicate the importance of Zfpm2 in the normal looping and septation of the heart and suggest a genetic basis for the syndrome of tricuspid atresia [1].
• Gata4(ki/ki) mice die just after embryonic day (E) 12.5 exhibiting features in common with Fog2(-/-) embryos as well as additional semilunar cardiac valve defects and a double-outlet right ventricle [2].
• FOG-2(-/-) embryos die at midgestation with a cardiac defect characterized by a thin ventricular myocardium, common atrioventricular canal, and the tetralogy of Fallot malformation [3].

High impact information on Zfpm2

• Zfpm2 interacts specifically with the N-terminal zinc finger of Gata4 and represses Gata4-dependent transcription [1].
• Here we use targeted mutagenesis to explore the role of Zfpm2 in normal cardiac development [1].
• FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium [3].
• Transgenic reexpression of FOG-2 in cardiomyocytes rescues the FOG-2(-/-) vascular phenotype, demonstrating that FOG-2 function in myocardium is required and sufficient for coronary vessel development [3].
• Likewise, FOG-2 is coexpressed with the GATA-4/5/6 subfamily at other sites, including the heart and gonads [4].

Biological context of Zfpm2

• COUP-TF2-null embryos die during embryonic development with defective angiogenesis and cardiac defects, a pattern that partly resembles the FOG-2-null phenotype [5].
• Gene targeting studies have demonstrated that FOG-2 is required for normal cardiac morphogenesis, including the development of the coronary vasculature, left ventricular compact zone, and heart valves [5].
• The properties of FOG-2 suggest its involvement in the control of cardiac and neural gene expression by GATA transcription factors [6].
• We found no difference in the ability of the endocardial cushions to undergo myocardialization or in the rates of mesenchymal cell proliferation, differentiation, or apoptosis in the FOG-2 deficient cushions when compared to wild-type controls [7].
• 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 [8].

Anatomical context of Zfpm2

• We found that Sry transcript levels were significantly reduced in XY Fog2(-/-) gonads at E11.5, which is the time when Sry expression normally reaches its peak [9].
• Mouse fetuses homozygous for a null allele of Fog2 or homozygous for a targeted mutation in Gata4 (Gata4(ki)) that abrogates the interaction of GATA4 with FOG co-factors exhibit abnormalities in gonadogenesis [9].
• 5. The other member of the mammalian FOG family, FOG-2, was not detected in gastric epithelium [10].
• The interaction between COUP-TF2 and FOG-2 in mammalian cells was confirmed by co-immunoprecipitation of these proteins from transfected COS-7 cells [5].
• We describe a novel FOG-related factor, FOG-2, that is expressed predominantly in the developing and adult heart, brain, and testis [6].

Associations of Zfpm2 with chemical compounds

• Fog2 (Zfpm2) maps within the recombinant interval carrying the N-ethyl-N-nitrosourea-induced mutation, and DNA sequencing of Fog2 identified a mutation in a splice donor site that generates an abnormal transcript encoding a truncated protein [11].

Regulatory relationships of Zfpm2

• Zfpm2 (also known as Fog-2) is a multi-zinc-finger protein that is co-expressed with Gata4 in the developing heart beginning at E8.5 (refs 8-10) [1].

Other interactions of Zfpm2

• Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2 [9].
• Full-length FOG-2 markedly enhanced transcriptional repression by GAL4-COUP-TF2(117-414), but not by a COUP-TF2 repression domain mutant [5].
• Further transient-transfection assays of various mutant promoters established the functional relevance of the Gata4-response and unknown factor-response elements, while studies of Dmrt1 expression in 13.5 days postcoitum Fog2 null gonads supported the in vivo importance of Gata4's regulation [12].
• Friend of GATA-1 (FOG-1) interacts with GATA-1 and is expressed principally in hematopoietic lineages, whereas FOG-2 is expressed predominantly in heart and brain [13].
• Remarkably, though FOG-2 is quite divergent from FOG in its primary sequence, forced expression of FOG-2 rescues terminal erythroid maturation of FOG-/- hematopoietic cells [14].

References