title: Mature erythrocyte membrane homeostasis is compromised by loss of the GATA1-FOG1 interaction.
abstract: GATA1 plays essential roles in erythroid gene expression. The N-terminal finger of GATA1 (GATA1-Nf) is important for association with FOG1. Substitution mutations in GATA1-Nf, such as GATA1(V205M) that diminish the GATA1-FOG1 association, have been identified in human thrombocytopenia and anemia cases. A mouse model of human thrombocytopenia has been established using a transgenic complementation rescue approach; GATA1-deficient mice were successfully rescued from embryonic lethality by excess expression of GATA1(V205G), but rescued adult mice suffered from severe thrombocytopenia. In this study, we examined GATA1-deficient mice rescued with GATA1(V205G) at a comparable level to endogenous GATA1. Mice rescued with this level of GATA1(V205G) rarely survive to adulthood. Rescued newborns suffered from severe anemia and jaundice accompanied with anisocytosis and spherocytosis. Expression of Slc4a1, Spna1, and Aqp1 genes (encoding the membrane proteins band-3, α-spectrin, and aquaporin-1, respectively) were strikingly diminished, whereas expression of other canonical GATA1-target genes, such as Alas2, were little affected. Lack of these membrane proteins provoked perturbation of membrane skeleton. Importantly, the red cells exhibited increased reactive oxygen species accumulation. These results thus demonstrate that the loss of the GATA1-FOG1 interaction causes a unique combination of membrane protein deficiency and disturbs the function of GATA1 in maintaining erythroid homeostasis.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Shimizu
authors.forename: Narla
authors.initials: N
authors.lastname: Mohandas
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000328:Adult; D000740:Anemia / Q000209:etiology / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004910:Erythrocyte Membrane / Q000502:physiology*; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology; D005434:Flow Cytometry; D050982:GATA1 Transcription Factor / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013921:Thrombocytopenia / Q000209:etiology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
chemical_list: D050982:GATA1 Transcription Factor; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C498432:ZFPM1 protein, human; C107310:Zfpm1 protein, mouse