title: Blimp-1/Prdm1 alternative promoter usage during mouse development and plasma cell differentiation.
abstract: The zinc-finger PR domain transcriptional repressor Blimp-1/Prdm1 plays essential roles in primordial germ cell specification, placental, heart, and forelimb development, plasma cell differentiation, and T-cell homeostasis. The present experiments demonstrate that the mouse Prdm1 gene has three alternative promoter regions. All three alternative first exons splice directly to exon 3, containing the translational start codon. To examine possible cell-type-specific functional activities in vivo, we generated targeted deletions that selectively eliminate two of these transcriptional start sites. Remarkably, mice lacking the previously described first exon develop normally and are fertile. However, this region contains NF-kappaB binding sites, and as shown here, NF-kappaB signaling is required for Prdm1 induction. Thus, mutant B cells fail to express Prdm1 in response to lipopolysaccharide stimulation and lack the ability to become antibody-secreting cells. An alternative distal promoter located approximately 70 kb upstream, giving rise to transcripts strongly expressed in the yolk sac, is dispensable. Thus, the deletion of exon 1B has no noticeable effect on expression levels in the embryo or adult tissues. Collectively, these experiments provide insight into the organization of the Prdm1 gene and demonstrate that NF-kappaB is a key mediator of Prdm1 expression.
authors.affiliation: University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, United Kingdom.
authors.forename: Marc A J
authors.initials: MA
authors.lastname: Morgan
authors.forename: Erna
authors.initials: E
authors.lastname: Magnusdottir
authors.forename: Tracy C
authors.initials: TC
authors.lastname: Kuo
authors.forename: Chai
authors.initials: C
authors.lastname: Tunyaplin
authors.forename: James
authors.initials: J
authors.lastname: Harper
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Arnold
authors.forename: Kathryn
authors.initials: K
authors.lastname: Calame
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Robertson
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Bikoff
mesh_terms: D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics*; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006579:Heterozygote; D007438:Introns / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010950:Plasma Cells / Q000166:cytology* / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site; D015533:Transcriptional Activation
chemical_list: D016328:NF-kappa B; C513258:Prdm1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1