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Heon Park,
Karen Staehling,
Mark Tsang, Mark W Appleby,
Mary E Brunkow,
Daciana Margineantu,
David M Hockenbery,
Tania Habib,
H Denny Liggitt,
George Carlson,
Brian M Iritani
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ABSTRACT: The coordination of nutrient and energy availability with cell growth and division is essential for proper immune cell development and function. By using a chemical mutagenesis strategy in mice, we identified a pedigree that has a complete block in B cell development at the pre-B cell stage resulting from a deletion in the Fnip1 gene. Enforced expression of an immunoglobulin transgene failed to rescue B cell development. Whereas essential pre-B cell signaling molecules were activated normally in Fnip1-null pre-B cells, the metabolic regulators AMPK and mTOR were dysregulated, resulting in excessive cell growth and enhanced sensitivity to apoptosis in response to metabolic stress (pre-B cell receptor crosslinking, oncogene activation). These results indicate that Folliculin-interacting protein 1 (Fnip1) is vital for B cell development and metabolic homeostasis and reveal a metabolic checkpoint that may ensure that pre-B cells have sufficient metabolic capacity to support division, while limiting lymphomagenesis caused by deregulated growth.
Immunity 05/2012; 36(5):769-81. · 21.64 Impact Factor
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Heon Park,
Karen Staehling-Hampton, Mark W Appleby,
Mary E Brunkow,
Tania Habib,
Yi Zhang,
Fred Ramsdell,
H Denny Liggitt,
Brian Freie,
Mark Tsang,
George Carlson,
Sherree Friend,
Charles Frevert,
Brian M Iritani
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ABSTRACT: Hem1 (Hematopoietic protein 1) is a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins. Orthologues of Hem1 in Dictyostelium discoideum, Drosophila melanogaster, and Caenorhabditis elegans are essential for cytoskeletal reorganization, embryonic cell migration, and morphogenesis. However, the in vivo functions of mammalian Hem1 are not known. Using a chemical mutagenesis strategy in mice to identify novel genes involved in immune cell functions, we positionally cloned a nonsense mutation in the Hem1 gene. Hem1 deficiency results in defective F-actin polymerization and actin capping in lymphocytes and neutrophils caused by loss of the Rac-controlled actin-regulatory WAVE protein complex. T cell development is disrupted in Hem1-deficient mice at the CD4(-)CD8(-) (double negative) to CD4(+)CD8(+) (double positive) cell stages, whereas T cell activation and adhesion are impaired. Hem1-deficient neutrophils fail to migrate in response to chemotactic agents and are deficient in their ability to phagocytose bacteria. Remarkably, some Rac-dependent functions, such as Th1 differentiation and nuclear factor kappaB (NF-kappaB)-dependent transcription of proinflammatory cytokines proceed normally in Hem1-deficient mice, whereas the production of Th17 cells are enhanced. These results demonstrate that Hem1 is essential for hematopoietic cell development, function, and homeostasis by controlling a distinct pathway leading to cytoskeletal reorganization, whereas NF-kappaB-dependent transcription proceeds independently of Hem1 and F-actin polymerization.
Journal of Experimental Medicine 12/2008; 205(12):2899-913. · 13.85 Impact Factor
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Leon F García-Martínez, Mark W Appleby,
Karen Staehling-Hampton,
Dawn M Andrews,
Yuching Chen,
Mark McEuen,
Phuong Tang,
Rebecca L Rhinehart,
Sean Proll,
Bryan Paeper,
Mary E Brunkow,
Andres G Grandea,
Edward D Howard,
Don E Walker,
Patrick Charmley,
Mechthild Jonas,
Stevan Shaw,
John A Latham,
Fred Ramsdell
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ABSTRACT: Using a mouse mutagenesis screen, we have identified CD83 as being critical for the development of CD4(+) T cells and for their function postactivation. CD11c(+) dendritic cells develop and function normally in mice with a mutated CD83 gene but CD4(+) T cell development is substantially reduced. Additionally, we now show that those CD4(+) cells that develop in a CD83 mutant animal fail to respond normally following allogeneic stimulation. This is at least in part due to an altered cytokine expression pattern characterized by an increased production of IL-4 and IL-10 and diminished IL-2 production. Thus, in addition to its role in selection of CD4(+) T cells, absence of CD83 results in the generation of cells with an altered activation and cytokine profile.
The Journal of Immunology 10/2004; 173(5):2995-3001. · 5.79 Impact Factor
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ABSTRACT: The completion of the genome sequences of both humans and mice challenges biologists to determine gene function on a vast, whole-organism scale. Both phenotype-based ('forward') and gene-based ('reverse') strategies are being developed to approach this issue. Forward-genetic approaches, however, provide the unique ability of assigning function to genes in an unbiased, global manner that is independent of previous assumptions about gene function. In this article, we compare various genetic technologies for their potential role in dissecting immune-system development and function, with particular emphasis on the worldwide efforts that use chemical mutagenesis as a forward-genetic strategy.
Nature reviews. Immunology 07/2003; 3(6):463-71. · 33.29 Impact Factor
