Perinatal synthetic lethality and hematopoietic defects in compound mafG :mafK mutant mice

Prior studies exploring the mechanisms controlling erythroid gene regulatio n implicated MARE (Maf recognition element) cis-elements as crucial to the transcriptional activity of many erythroid genes, Numerous transcription fa ctors can elicit responses through MAREs, including not only the AP-1 famil y proteins, but also a growing list of factors composed of Cap-N-Collar (CN C)-small Maf heterodimers, While these factors can activate transcription f rom 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 deficien cies. First, compound homozygous small maf gene mutants survive embryogenes is, but die postnatally, Secondly, compound mutant animals develop severe n eurological disorders, Thirdly, they exhibit an exacerbated mafG deficiency in megakaryopoiesis, specifically in proplatelet formation, resulting in p rofound thrombocytopenia, Finally, the compound mutant animals develop seve re anemia accompanied by abnormal erythrocyte morphology and membrane prote in composition, These data provide direct evidence that the small Maf trans cription factors play an important regulatory role in erythropoiesis.