The P4-type ATPase ATP11C is essential for B lymphopoiesis in adult bone marrow

Abstract

B lymphopoiesis begins in the fetal liver, switching after birth to the bone marrow, where it persists for life. The unique developmental outcomes of each phase are well documented, yet their molecular requirements are not. Here we describe two allelic X-linked mutations in mice that caused cell-intrinsic arrest of adult B lymphopoiesis. Mutant fetal liver progenitors generated B cells in situ but not in irradiated adult bone marrow, which emphasizes a necessity for the affected pathway only in the context of adult bone marrow. The causative mutations were ascribed to Atp11c, which encodes a P4-type ATPase with no previously described function. Our data establish an essential, cell-autonomous and context-sensitive function for ATP11C, a putative aminophospholipid flippase, in B cell development.

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Figure 1: A heritable B cell deficiency.
Figure 2: Immunoglobulin secretion in emptyhive mice.
Figure 3: A cell-intrinsic failure of adult B cell development.
Figure 4: Sensitivity to IL-7 and a failure to sustain expression of Ebf1.
Figure 5: Partial correction of the emptyhive phenotype by BCR transgenes.
Figure 6: The emptyhive phenotype is caused by a recessive mutation of Atp11c.
Figure 7: Intact B lymphopoiesis in fetal liver.

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Acknowledgements

We thank M. Gutierrez for animal care; T. Robinson, S. Kalina and C. Ross for genotyping; C. Goodnow (John Curtin School of Medical Research) and R. Brink (Garvan Institute) for mice; A. Feeney for discussions; and D. La Vine for Figure 6f. Supported by the Bill & Melinda Gates Foundation, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (HHSN272200700038C to (B.B.), The General Sir John Monash Foundation (O.M.S.) and the Cancer Research Institute (C.N.A.).

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O.M.S. designed and did experiments, analyzed data and wrote the paper under the guidance of B.B.; C.N.A. and E.P. identified the spelling phenotype and assisted with immunization experiments; Y.X. and P.L. assisted with positional cloning and mutation identification; and C.H. measured immunoglobulin isotypes with reagents that D.N. contributed.

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Correspondence to Bruce Beutler.

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The authors declare no competing financial interests.

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Siggs, O., Arnold, C., Huber, C. et al. The P4-type ATPase ATP11C is essential for B lymphopoiesis in adult bone marrow. Nat Immunol 12, 434–440 (2011). https://doi.org/10.1038/ni.2012

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