THE BZIP TRANSCRIPTION FACTOR LCR-F1 IS ESSENTIAL FOR MESODERM FORMATION IN MOUSE DEVELOPMENT

LCR-F1 is a mammalian bZIP transcription factor containing a basic ami no acid domain highly homologous to a domain in the Drosophila Cap 'N' Collar and Caenorhabditis elegans SKN-1 proteins. LCR-F1 binds to AP1 -like sequences in the human P-globin locus control region and activat es high-level expression of p-globin genes. To assess the role of LCR- F1 in mammalian development, the mouse Lcrf1 gene was deleted in embry onic stem (ES) cells, and mice derived from these cells were mated to produce Lcrf1 null animals. Homozygous mutant embryos progressed norma lly to the late egg cylinder stage at similar to 6.5 days post coitus (dpc), but development was arrested before 7.5 dpc. Lcrf1 mutant embry os failed to form a primitive streak and lacked detectable mesoderm. T hese results demonstrate that LCR-F1 is essential for gastrulation in the mouse and suggest that this transcription factor controls expressi on of genes critical for the earliest events in mesoderm formation. In terestingly, Lcrf1 null ES cells injected into wild-type blastocysts c ontributed to all mesodermally derived tissues examined, including ery throid cells producing hemoglobin. These results demonstrate that the Lcrf1 mutation is not cell autonomous and suggest that LCR-F1 regulate s expression of signaling molecules essential for gastrulation. The sy nthesis of normal hemoglobin levels in erythroid cells of chimeras der ived from Lcrf1 null cells suggests that LCR-F1 is not essential for g lobin gene expression. LCR-F1 and the related bZIP transcription facto rs NE-E2 p45 and NRF2 must compensate for each other in globin gene re gulation.