Early B Cell Progenitors Deficient for GON4L Fail To Differentiate Due to a Block in Mitotic Cell Division
| Autor: | Jennifer Y. Barr, Renee X. Goodfellow, Diana F. Colgan, John D. Colgan |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell division Cellular differentiation Immunology Cyclin A Cyclin B Mitosis Cell Cycle Proteins E2F4 Transcription Factor Article 03 medical and health sciences Mice Immunology and Allergy Animals Progenitor cell Cyclin D3 Cell Proliferation B-Lymphocytes biology Cell growth Interleukin-7 Precursor Cells B-Lymphoid Cell Cycle Nuclear Proteins Cell cycle Cell biology DNA-Binding Proteins 030104 developmental biology Gene Expression Regulation biology.protein Co-Repressor Proteins Cell Division |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 198(10) |
| ISSN: | 1550-6606 |
| Popis: | B cell development in Justy mutant mice is blocked due to a precursor mRNA splicing defect that depletes the protein GON4-like (GON4L) in B cell progenitors. Genetic and biochemical studies have suggested that GON4L is a transcriptional regulator that coordinates cell division with differentiation, but its role in B cell development is unknown. To understand the function of GON4L, we characterized B cell differentiation, cell cycle control, and mitotic gene expression in GON4L-deficient B cell progenitors from Justy mice. We found that these cells established key aspects of the transcription factor network that guides B cell development and proliferation and rearranged the IgH gene locus. However, despite intact IL-7 signaling, GON4L-deficient pro-B cell stage precursors failed to undergo a characteristic IL-7–dependent proliferative burst. These cells also failed to upregulate genes required for mitotic division, including those encoding the G1/S cyclin D3 and E2F transcription factors and their targets. Additionally, GON4L-deficient B cell progenitors displayed defects in DNA synthesis and passage through the G1/S transition, contained fragmented DNA, and underwent apoptosis. These phenotypes were not suppressed by transgenic expression of prosurvival factors. However, transgenic expression of cyclin D3 or other regulators of the G1/S transition restored pro-B cell development from Justy progenitor cells, suggesting that GON4L acts at the beginning of the cell cycle. Together, our findings indicate that GON4L is essential for cell cycle progression and division during the early stages of B cell development. |
| Databáze: | OpenAIRE |
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