Early B Cell Progenitors Deficient for GON4L Fail To Differentiate Due to a Block in Mitotic Cell Division

Jennifer Y Barr; Renee X Goodfellow; Diana F Colgan; John D Colgan

doi:10.4049/jimmunol.1602054

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Early B Cell Progenitors Deficient for GON4L Fail To Differentiate Due to a Block in Mitotic Cell Division

Journal article

Peer reviewed

Early B Cell Progenitors Deficient for GON4L Fail To Differentiate Due to a Block in Mitotic Cell Division

Jennifer Y Barr, Renee X Goodfellow, Diana F Colgan and John D Colgan

The Journal of immunology (1950), Vol.198(10), pp.3978-3988

05/15/2017

DOI: 10.4049/jimmunol.1602054

PMCID: PMC5444326

PMID: 28381640

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Abstract

B cell development in 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 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 G /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 G /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 G /S transition restored pro-B cell development from 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.

Cell Proliferation

Mitosis

Gene Expression Regulation

B-Lymphocytes - physiology

E2F4 Transcription Factor - genetics

Animals

Interleukin-7 - immunology

Cell Cycle

Cell Division

Cyclin D3 - genetics

Nuclear Proteins - deficiency

Mice

Nuclear Proteins - physiology

Nuclear Proteins - genetics

Precursor Cells, B-Lymphoid - physiology

E2F4 Transcription Factor - metabolism

Cell Cycle Proteins

Interleukin-7 - metabolism

Details

Title: Subtitle: Early B Cell Progenitors Deficient for GON4L Fail To Differentiate Due to a Block in Mitotic Cell Division
Creators: Jennifer Y Barr - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Renee X Goodfellow - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242; and
Diana F Colgan - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242; and
John D Colgan - Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.198(10), pp.3978-3988
DOI: 10.4049/jimmunol.1602054
PMID: 28381640
PMCID: PMC5444326
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Grant note: R56 AI093737 / NIAID NIH HHS S10 RR027219 / NCRR NIH HHS R01 AI054821 / NIAID NIH HHS R01 AI093737 / NIAID NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 05/15/2017
Academic Unit: Anatomy and Cell Biology; Immunology; Otolaryngology; Internal Medicine
Record Identifier: 9984025423702771

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