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

Department of Genetics, The Scripps Research Institute, La Jolla, California, USA.
Nature Immunology (Impact Factor: 20). 03/2011; 12(5):434-40. DOI: 10.1038/ni.2012
Source: PubMed


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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    • "Similarly, absence of the signaling cascade components that follow IL-7R activation such as STAT5 (A and B) (Goetz et al. 2004; Yao et al. 2006), cyclin D3 (Cooper et al. 2006), and phosphoinositide 3-kinase (PI3K) (Ramadani et al. 2010; Fruman et al. 1999; Suzuki et al. 1999; Clayton et al. 2002; Jou et al. 2002; Okkenhaug et al. 2002) greatly attenuate the proliferation and survival of pre-B cells. Interestingly, mutation in ATP11c, a P4 ATPases (flippase) that is required for IL-7 signaling, results in a progressive loss of pro-and pre-B cells (Clark 2011; Pang and Nutt 2011; Siggs et al. 2011; Yabas et al. 2011). Clearly, efficient pre-B cell differentiation requires the coordination of the intrinsic cell differentiation program, appropriate recombination of the Igh and Igl genes, and responsiveness to extrinsic signals provided by cytokines (IL-7 in the mouse). "
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    Current topics in microbiology and immunology 05/2014; 381. DOI:10.1007/82_2014_377 · 4.10 Impact Factor
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    • "The mouse ATP10A gene (also called ATP10C) is linked to diet-induced obesity and type II diabetes phenotypes [36], and an ATP10D mutation shows linkage to a fat-prone phenotype in certain strains of mice [37,38]. Recently, ATP11C has been shown to participate in the B lymphocyte differentiation [39,40]. Together, these observations imply that the asymmetric distribution of phospholipids in biological membranes maintained/regulated by P4-ATPases plays crucial roles in mammalian pathophysiology. "
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    • "Hematopoietic stem and progenitor cells (HSPC) derived from the middle-stage FL still lacked estrogen receptors even four weeks after transplantation to irradiated RAG-1-deficient mice (Igarashi et al., 2001). An increasing body of evidence has provided information on the differences between FL and adult-BM hematopoietic cells (Bowie et al., 2007; Hardy and Hayakawa, 1991; Hardy et al., 2007; Irion et al., 2010; Medina and Kincade, 1994; Montecino-Rodriguez et al., 2006; Siggs et al., 2011). Kikuchi et al. (2005) have demonstrated that regarding the IL-7 receptor expression, the conversion from FL phenotype to adult phenotype occurs in mice during the first few weeks after birth. "
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