title: Independent regulation of the two Pax5 alleles during B-cell development.
abstract: The developmental control genes of the Pax family are frequently associated with mouse mutants and human disease syndromes. The function of these transcription factors is sensitive to gene dosage, as mutation of one allele or a modest increase in gene number results in phenotypic abnormalities. Pax5 has an important role in B-cell and midbrain development. By following the expression of individual Pax5 alleles at the single-cell level, we demonstrate here that Pax5 is subject to allele-specific regulation during B-lymphopoiesis. Pax5 is predominantly transcribed from only one allele in early progenitors and mature B cells, whereas it switches to a biallelic transcription mode in immature B cells. The allele-specific regulation of Pax5 is stochastic, reversible, independent of parental origin and correlates with synchronous replication, in contrast with imprinted and other monoallelically expressed genes. As a consequence, B-lymphoid tissues are mosaics with respect to the transcribed Pax5 allele, and thus mutation of one allele in heterozygous mice results in deletion of the cell population expressing the mutant allele due to loss of Pax5 function at the single-cell level. Similar allele-specific regulation may be a common mechanism causing the haploinsufficiency and frequent association of other Pax genes with human disease.
authors: Research Institute of Molecular Pathology, Vienna, Austria.
authors: S L
authors: SL
authors: Nutt
authors: S
authors: S
authors: Vambrie
authors: P
authors: P
authors: Steinlein
authors: Z
authors: Z
authors: Kozmik
authors: A
authors: A
authors: Rolink
authors: A
authors: A
authors: Weith
authors: M
authors: M
authors: Busslinger
mesh_terms: D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001853:Bone Marrow / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051740:Ikaros Transcription Factor; D017404:In Situ Hybridization, Fluorescence; D008099:Liver / Q000166:cytology / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051757:PAX5 Transcription Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D014157:Transcription Factors; D051740:Ikaros Transcription Factor