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ABSTRACT: HSC function depends on the tight control of proliferation and the balance between self-renewal and differentiation. Here, we report that the trimeric transcription factor NF-Y is critical for the survival of cycling, but not quiescent HSCs. With the use of a conditional knockout mouse model, we demonstrate that NF-Ya deletion creates an accumulation of HSCs in G(2)/M and prompts apoptosis, causing hematopoietic failure and death of the animal. These defects are accompanied by the dysregulation of multiple genes that influence cell cycle control (cyclin b1 and p21), apoptosis (Bcl-2), and self-renewal (HoxB4, Notch1, Bmi-1) and are independent of p53. Our results identify NF-Y as a pivotal upstream participant in a regulatory network necessary for the preservation of cycling HSCs.
Blood 11/2011; 119(6):1380-9. · 9.90 Impact Factor
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Tatjana Dorn,
Ursula Kuhn, Gerd Bungartz,
Sebastian Stiller,
Martina Bauer,
Joachim Ellwart,
Thorsten Peters,
Karin Scharffetter-Kochanek,
Monika Semmrich,
Melanie Laschinger,
Bernhard Holzmann,
Wolfgang E F Klinkert,
Per Thor Straten,
Tania Køllgaard,
Michael Sixt,
Cord Brakebusch
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ABSTRACT: RhoH is a small GTPase expressed only in the hematopoietic system. With the use of mice with targeted disruption of the RhoH gene, we demonstrated that RhoH is crucial for thymocyte maturation during DN3 to DN4 transition and during positive selection. Furthermore, the differentiation and expansion of DN3 and DN4 thymocytes in vitro were severely impaired. These defects corresponded to defective TCR signaling. Although RhoH is not required for TCR-induced activation of ZAP70 and ZAP70-mediated activation of p38, it is crucial for the tyrosine phosphorylation of LAT, PLCgamma1, and Vav1 and for the activation of Erk and calcium influx. These data suggest that RhoH is important for pre-TCR and TCR signaling because it allows the efficient interaction of ZAP70 with the LAT signalosome, thus regulating thymocyte development.
Blood 04/2007; 109(6):2346-55. · 9.90 Impact Factor
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ABSTRACT: The function of alpha4beta1 and alpha4beta7 integrins in hematopoiesis is controversial. While some experimental evidence suggests a crucial role for these integrins in retention and expansion of progenitor cells and lymphopoiesis, others report a less important role in hematopoiesis. Using mice with a deletion of the beta1 and the beta7 integrin genes restricted to the hematopoietic system we show here that alpha4beta1 and alpha4beta7 integrins are not essential for differentiation of lymphocytes or myelocytes. However, beta1beta7 mutant mice displayed a transient increase of colony-forming unit (CFU-C) progenitors in the bone marrow and, after phenylhydrazine-induced anemia, a decreased number of splenic erythroid colony-forming units in culture (CFUe's). Array gene expression analysis of CD4(+)CD8(+) double-positive (DP) and CD4(-)CD8(-) double-negative (DN) thymocytes and CD19(+) and CD4(+) splenocytes did not provide any evidence for a compensatory mechanism explaining the mild phenotype. These data show that alpha4beta1 and alpha4beta7 are not required for blood cell differentiation, although in their absence alterations in numbers and distribution of progenitor cells were observed.
Blood 10/2006; 108(6):1857-64. · 9.90 Impact Factor
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ABSTRACT: beta(1) integrins are thought to play a central role in maintaining lymphocytes within mucosal epithelia via their interactions with extracellular matrix proteins and subepithelial cellular components within and underlying the basement membrane. In the current study type a (CD8alphabetaTCRalphabeta) and type b (CD8alphaalphaTCRgammadelta and CD8alphaalphaTCRalphabeta) intraepithelial lymphocyte (IEL) subsets within the mouse small intestine were found to express functional beta(1) integrin and the beta(1) integrin alpha chain partners alpha(1), alpha(2), and alpha(4). Using inducible beta(1) integrin-knockout bone marrow-chimeric mice we demonstrate that IEL expression of alpha(1) and alpha(2) but not alpha(4) is dependent on expression of the beta(1) chain. Importantly, deletion of the beta(1) chain in IEL did not alter the number or composition of lymphocytes within the intestinal epithelium. Thus, while IEL express functional beta(1) integrins, these are not required to maintain lymphocytes within intestinal epithelia. This result is discussed in the light of conventional views of intestinal lymphocyte homing and localization.
European Journal of Immunology 07/2005; 35(6):1805-11. · 5.10 Impact Factor
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ABSTRACT: Several experimental evidences suggested that beta1 integrin-mediated adhesion of hematopoietic stem cells (HSC) is important for their function in the bone marrow (BM). Using induced deletion of the beta1 integrin gene restricted to the hematopoietic system, we show that beta1 integrin is not essential for HSC retention in the BM, hematopoiesis, and trafficking of lymphocytes. However, immunization with a T cell-dependent antigen resulted in virtually no IgM production and an increased secretion of IgG in mutant mice, while the response to a T cell-independent type 2 antigen showed decreases in both IgM and IgG. These data suggest that beta1 integrins are necessary for the primary IgM antibody response.
Immunity 04/2002; 16(3):465-77. · 21.64 Impact Factor
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Gerd. Bungartz
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Gerd Bungartz
