The importance of resting phases in B cell development
Everyone preparing for the London Marathon likely knows that to perform their best during the event, they need to rest up now. Research at the Babraham Institute just published in the journal Science describes a new mechanism through which B cells ensure that they rest up between intensive developmental events.
Just as our daily routine involves periods of activity, nourishment and rest, the cell cycle describes states that the cell progresses through leading to its division into two daughter cells. Like when we take a holiday, the cell can also pause and take a break after a cell division and this is what researchers call quiescence – a reversible sedentary state.
Researchers at the Institute took a deeper look into how B cells, the immune cells that make antibodies, progress through important developmental stages. In particular they looked at the role of two proteins and how these are able to impose rest periods (quiescence) on cells to ensure that developing B cells ‘grow up’ properly. The researchers showed that without these rest periods, B cells didn’t survive to become functional immune cells. In mice, a 98% reduction of mature B cells was seen when the cells lacked these proteins.
Dr Alison Galloway, first author on the paper and postdoctoral researcher at the Babraham Institute, explained: “We found that the two proteins, RNA binding proteins ZFP36L1 and ZFP36L2, promote cell quiescence by blocking the RNA messages telling the cells to start dividing again. In the same way that we find it hard to function without sleep, the B cells don’t develop as they should if these cell cycle pauses are lost.”
Dr Martin Turner, senior author on the paper and Head of the Lymphocyte Signalling and Development research programme at the Institute, commented: “Although roles for transcription factors in establishing quiescence have been established, the contribution of sequence-specific RNA binding proteins was unknown. Our findings shed light on the intricate control and coordination of the cell cycle and show that these binding proteins probably form part of a common mechanism to regulate quiescence, not just one specific to developing B cells.”
This research was supported by the Biotechnology and Biological Sciences Research Council, the Medical Research Council, and project grants from the charity Bloodwise (previously Leukaemia & Lymphoma Research).
Fluorescent microscopy image showing VDJ recombination (rearrangement of antigen receptor genes) in a B cell. VDJ recombination is one of the processes affected by loss of the cell cycle rest phases. Nuclear DNA visualised with Dapi in blue. VH-DH intergenic regions are detected in red. Igh constant region is detected in green. Image: Daniel Bolland, Babraham Institute.
Affiliated authors (in author order):
Alison Galloway, postdoctoral researcher (Turner lab)
Alexander Saveliev, postdoctoral researcher (Turner lab)
Sebastian Łukasiak, postdoctoral researcher (Turner lab)
Daniel J. Hodson, clinician scientist (University of Cambridge)
Daniel Bolland, senior research associate, (Corcoran lab)
Kathryn Balmanno, senior research scientist (Cook lab)
Helena Ahlfors, postdoctoral researcher (Turner lab)
Elisa Monzón-Casanova, postdoctoral researcher (Turner lab)
Sara Ciullini Mannurita, Da Vinci scholar (Turner lab)
Lewis S. Bell, PhD student (Turner lab)
Simon Andrews, Head of Bioinformatics facility
Manuel D. Díaz-Muñoz, postdoctoral researcher (Turner lab)
Simon J. Cook, group leader, Signalling programme
Anne Corcoran, group leader, Nuclear Dynamics programme
Martin Turner, Head of the Lymphocyte Signalling and Development programme
Galloway et al. (2016) RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence. Science
Animal research statement:
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here used genetically modified mice lacking the two genes encoding the RNA-binding proteins ZFP36L1 and ZFP36L2. Bone marrow was taken from these mice to analyse the effect on mature B cell development.
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