title: Perinatal synthetic lethality and hematopoietic defects in compound mafG::mafK mutant mice.
abstract: Prior studies exploring the mechanisms controlling erythroid gene regulation implicated MARE (Maf recognition element) cis-elements as crucial to the transcriptional activity of many erythroid genes. Numerous transcription factors can elicit responses through MAREs, including not only the AP-1 family proteins, but also a growing list of factors composed of Cap-N-Collar (CNC)-small Maf heterodimers. While these factors can activate transcription from MAREs in co-transfection assays, mouse germline mutations in cnc genes tested to date have failed to reveal primary erythroid phenotypes. Here we report that after combining the mafK and mafG targeted null alleles, mutant animals display several synthetic phenotypes, including erythroid deficiencies. First, compound homozygous small maf gene mutants survive embryogenesis, but die postnatally. Secondly, compound mutant animals develop severe neurological disorders. Thirdly, they exhibit an exacerbated mafG deficiency in megakaryopoiesis, specifically in proplatelet formation, resulting in profound thrombocytopenia. Finally, the compound mutant animals develop severe anemia accompanied by abnormal erythrocyte morphology and membrane protein composition. These data provide direct evidence that the small Maf transcription factors play an important regulatory role in erythropoiesis.
authors.affiliation: Department of Biochemistry, Northwestern University, Evanston, IL 60208-3500, USA.
authors.forename: K
authors.initials: K
authors.lastname: Onodera
authors.forename: J A
authors.initials: JA
authors.lastname: Shavit
authors.forename: H
authors.initials: H
authors.lastname: Motohashi
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: J D
authors.initials: JD
authors.lastname: Engel
mesh_terms: D000740:Anemia / Q000150:complications / Q000473:pathology; D000818:Animals; D001772:Blood Cell Count; D001792:Blood Platelets / Q000473:pathology; D002454:Cell Differentiation; D048429:Cell Size; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D004912:Erythrocytes / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D005786:Gene Expression Regulation / Q000235:genetics; D005804:Genes, Lethal / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006720:Homozygote; D051259:MafG Transcription Factor; D050985:MafK Transcription Factor; D008297:Male; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D009422:Nervous System Diseases / Q000150:complications / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D013921:Thrombocytopenia / Q000150:complications / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D051259:MafG Transcription Factor; D050985:MafK Transcription Factor; C491247:Mafg protein, mouse; D009687:Nuclear Proteins; D012097:Repressor Proteins