Abstract
The polycistronic mir-17-92 cluster, also known as oncomir-1, was previously shown to be essential for early B lymphopoiesis. However, its role in late-stage B-cell differentiation and function remains unexplored. Here we ablate mir-17-92 in mature B cells and demonstrate that mir-17-92 is dispensable for conventional B-cell development in the periphery. Interestingly, mir-17-92-deficiency in B cells leads to enhanced homing of plasma cells to the bone marrow during T-cell-dependent immune response and selectively impairs IgG2c production. Mechanistically, mir-17-92 directly represses the expression of Sphingosine 1-phosphate receptor 1 and transcription factor IKAROS, which are, respectively, important for plasma cell homing and IgG2c production. We further show that deletion of mir-17-92 could reduce IgG2c anti-DNA autoantibody production and hence mitigate immune complex glomerulonephritis in Shp1-deficient mice prone to autoimmunity. Our results identify important roles for mir-17-92 in the regulation of peripheral B-cell function.
Highlights
The polycistronic mir-17–92 cluster, known as oncomir-1, was previously shown to be essential for early B lymphopoiesis
We reveal that immunoglobulin G2c (IgG2c) production is impaired in the absence of mir-17–92 and this defect is due to increased expression of the transcription factor IKAROS, which is important for IgG2c production[20] and directly repressed by mir-92a
Fluorescence-activated sorting (FACS) analyses revealed that the frequency and numbers of pro-B (B220 þ CD43 þ IgM À ) and pre-B (B220 þ CD43 À IgM À ) cells were comparable in the bone marrow (BM) of mir-17–92 þ / þ Cd19Cre/ þ and mir-17–92fl/flCd19Cre/ þ
Summary
The polycistronic mir-17–92 cluster, known as oncomir-1, was previously shown to be essential for early B lymphopoiesis. When Dicer was deleted at the earliest stage of B-cell maturation using mb-1 Cre, B lymphopoiesis was severely blocked at the pro-B to pre-B-cell transition[11] This defect was mainly attributed to the absence of mir-17–92 whose seed sequences were enriched in the 30-untranslated regions (30UTRs) of mRNAs upregulated in Dicer-deficient pro-B cells[11]. We show that five out of six members of mir-17–92 cluster directly target the 30UTR of S1pr[1] and removal of one S1pr[1] allele could rebalance S1pr[1] expression and normalize the enhanced BM homing phenotype of mir-17–92deficient PCs. We reveal that immunoglobulin G2c (IgG2c) production is impaired in the absence of mir-17–92 and this defect is due to increased expression of the transcription factor IKAROS, which is important for IgG2c production[20] and directly repressed by mir-92a Our findings identify novel roles for mir-17–92 in regulating peripheral B-cell function by fine-tuning different target genes
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
