The Ig heavy chain protein but not its message controls early B cell development
| Autor: | Bingtao Hao, Heinz Jacobs, Colin Pritchard, Martijn van Baalen, Peter H.L. Krijger, Ron M. Kerkhoven, Iris de Rink, Mir Farshid Alemdehy, Muhammad Assad Aslam, Ika Nurzijah, Fitriari Izzatunnisa Muhaimin, Jane A. Skok, Paul C.M. van den Berk |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
early B cell development
Biology 03 medical and health sciences Exon 0302 clinical medicine Immunology and Inflammation allelic exclusion read-through translation medicine Animals RNA Messenger Allele B cell Alleles 030304 developmental biology 0303 health sciences Messenger RNA B-Lymphocytes Multidisciplinary Ig heavy chain checkpoint Precursor Cells B-Lymphoid RNA Reproducibility of Results Biological Sciences PreB cell antigen receptor Molecular biology Stop codon Mice Inbred C57BL Allelic exclusion medicine.anatomical_structure Genetic Loci Immunoglobulin heavy chain Immunoglobulin Heavy Chains 030217 neurology & neurosurgery Biomarkers |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Immunoglobulin heavy chain checkpoint (IgHCC) is a critical step during early B cell development. The role of immunoglobulin heavy chain (IgHC) at this step is well established. However, with the expanding knowledge of RNA in regulating central biological processes, there could be a noncoding contribution of IgHC mRNA (IgHR) in controlling the IgHCC. Here, we generated a novel mouse model that enabled us to determine a potential role of IgHR in the IgHCC, independent of IgHC signaling. Our data indicate that IgHR has no role in IgHCC and the latter is predominantly controlled by IgHC, as proposed earlier. Furthermore, this study highlights the sensitivity of progenitor B cells to low amounts of IgHC. Development of progenitor B cells (ProB cells) into precursor B cells (PreB cells) is dictated by immunoglobulin heavy chain checkpoint (IgHCC), where the IgHC encoded by a productively rearranged Igh allele assembles into a PreB cell receptor complex (PreBCR) to generate signals to initiate this transition and suppressing antigen receptor gene recombination, ensuring that only one productive Igh allele is expressed, a phenomenon known as Igh allelic exclusion. In contrast to a productively rearranged Igh allele, the Igh messenger RNA (mRNA) (IgHR) from a nonproductively rearranged Igh allele is degraded by nonsense-mediated decay (NMD). This fact prohibited firm conclusions regarding the contribution of stable IgHR to the molecular and developmental changes associated with the IgHCC. This point was addressed by generating the IghTer5H∆TM mouse model from IghTer5H mice having a premature termination codon at position +5 in leader exon of IghTer5H allele. This prohibited NMD, and the lack of a transmembrane region (∆TM) prevented the formation of any signaling-competent PreBCR complexes that may arise as a result of read-through translation across premature Ter5 stop codon. A highly sensitive sandwich Western blot revealed read-through translation of IghTer5H message, indicating that previous conclusions regarding a role of IgHR in establishing allelic exclusion requires further exploration. As determined by RNA sequencing (RNA-Seq), this low amount of IgHC sufficed to initiate PreB cell markers normally associated with PreBCR signaling. In contrast, the IghTer5H∆TM knock-in allele, which generated stable IgHR but no detectable IgHC, failed to induce PreB development. Our data indicate that the IgHCC is controlled at the level of IgHC and not IgHR expression. |
| Databáze: | OpenAIRE |
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