title: Targeted deletion of the gene encoding the La autoantigen (Sjögren's syndrome antigen B) in B cells or the frontal brain causes extensive tissue loss.
abstract: La antigen (Sjögren's syndrome antigen B) is a phosphoprotein associated with nascent precursor tRNAs and other RNAs, and it is targeted by autoantibodies in patients with Sjögren's syndrome, systemic lupus erythematosus, and neonatal lupus. Increased levels of La are associated with leukemias and other cancers, and various viruses usurp La to promote their replication. Yeast cells (Saccharomyces cerevisiae and Schizosaccharomyces pombe) genetically depleted of La grow and proliferate, whereas deletion from mice causes early embryonic lethality, raising the question of whether La is required by mammalian cells generally or only to surpass a developmental stage. We developed a conditional La allele and used it in mice that express Cre recombinase in either B cell progenitors or the forebrain. B cell Mb1(Cre) La-deleted mice produce no B cells. Consistent with αCamKII Cre, which induces deletion in hippocampal CA1 cells in the third postnatal week and later throughout the neocortex, brains develop normally in La-deleted mice until ∼5 weeks and then lose a large amount of forebrain cells and mass, with evidence of altered pre-tRNA processing. The data indicate that La is required not only in proliferating cells but also in nondividing postmitotic cells. Thus, La is essential in different cell types and required for normal development of various tissue types.
authors.affiliation: Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Gaidamakov
authors.forename: Olga A
authors.initials: OA
authors.lastname: Maximova
authors.forename: Hyongi
authors.initials: H
authors.lastname: Chon
authors.forename: Nathan H
authors.initials: NH
authors.lastname: Blewett
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Crawford
authors.forename: Amanda
authors.initials: A
authors.lastname: Day
authors.forename: Natalie
authors.initials: N
authors.lastname: Tulchin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Crouch
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.forename: Robert D
authors.initials: RD
authors.lastname: Blitzer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Maraia
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D005625:Frontal Lobe / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000276:immunology* / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D000097585:SS-B Antigen
chemical_list: D001324:Autoantigens; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D012313:RNA; D012322:RNA Precursors; D012343:RNA, Transfer; D012261:Ribonucleoproteins; D000097585:SS-B Antigen