Biomedical subjects

Jonathan Back

Publications and source records attributed to Jonathan Back.

4 recordsLinked to original sources

PubMed2005

Visualizing PU.1 activity during hematopoiesis.

OBJECTIVE: PU.1 is a critical transcription factor for hematopoietic development that is required for the early differentiation of myeloid, erythroid, and B lineage cells. To gain a better insight into PU.1 function, we performed a comprehensive analysis of PU.1 gene activity in the hematopoietic system, using a green fluorescent protein reporter mouse line. METHODS: We used flow cytometry to analyze green fluorescent protein (GFP) expression, along with various cell surface markers, in heterozygote mice that harbor a GFP reporter knocked into exon1 of the PU.1 gene. Phenotypic and functional properties of GFP+ and GFP- precursors were studied. RESULTS: We show that PU.1 is dynamically and heterogeneously expressed in many hematopoietic lineages, from the stem cell stage to terminally differentiated cells, suggesting that PU.1 is not only important in early differentiation events but also may play a role in mature hematopoietic cell function. Further, examination of GFP+ vs GFP- populations shows that differentiation, but not commitment, to the myeloid lineage requires PU.1. In contrast, B cell commitment is associated with low levels of PU.1 expression. CONCLUSION: Our study provides a detailed visualization of PU.1 gene activity in hematopoietic cells, and shows that highly dynamic regulation of PU.1 accompanies cell fate decisions during hematopoiesis.

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PubMed2004

Enhanced bone formation in lipodystrophic PPARgamma(hyp/hyp) mice relocates haematopoiesis to the spleen.

The peroxisome proliferator-activated receptor gamma (PPARgamma) controls adipogenesis and metabolism. We demonstrate here that the absence of PPARgamma in fat has potent osteogenic activities, which affect haematopoiesis. The congenital absence of PPARgamma in fat of lipodystrophic PPARgamma(hyp/hyp) mice, strongly enhanced bone mass and consequentially reduced the bone-marrow cavity. Consistent with this, PPARgamma(hyp/hyp) mice had a significant decrease in bone marrow cellularity and resorted to extramedullary haematopoiesis in the spleen to maintain haematopoiesis. Our data indicate that antagonizing PPARgamma activity in fat could be an effective way to combat osteoporosis and suggest that haematopoietic function should be scrutinized in lipodystrophic subjects.

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PubMed2004

PU.1 determines the self-renewal capacity of erythroid progenitor cells.

PU.1 is a hematopoietic-specific transcriptional activator that is absolutely required for the differentiation of B lymphocytes and myeloid-lineage cells. Although PU.1 is also expressed by early erythroid progenitor cells, its role in erythropoiesis, if any, is unknown. To investigate the relevance of PU.1 in erythropoiesis, we produced a line of PU.1-deficient mice carrying a green fluorescent protein reporter at this locus. We report here that PU.1 is tightly regulated during differentiation-it is expressed at low levels in erythroid progenitor cells and down-regulated upon terminal differentiation. Strikingly, PU.1-deficient fetal erythroid progenitors lose their self-renewal capacity and undergo proliferation arrest, premature differentiation, and apoptosis. In adult mice lacking one PU.1 allele, similar defects are detected following stress-induced erythropoiesis. These studies identify PU.1 as a novel and critical regulator of erythropoiesis and highlight the versatility of this transcription factor in promoting or preventing differentiation depending on the hematopoietic lineage.

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PubMed2002

The p53 tumour suppressor inhibits glucocorticoid-induced proliferation of erythroid progenitors.

Hypoxia encountered at high altitude, blood loss and erythroleukemia instigate stress erythropoiesis, which involves glucocorticoid-induced proliferation of erythroid progenitors (ebls). The tumour suppressor p53 stimulates hematopoietic cell maturation and antagonizes glucocorticoid receptor (GR) activity in hypoxia, suggesting that it may inhibit stress erythropoiesis. We report that mouse fetal liver ebls that lack p53 proliferate better than wild-type cells in the presence of the GR agonist dexamethasone. An important mediator of GR-induced ebl self-renewal, the c-myb gene, is induced to higher levels in p53(-/-) ebls by dexamethasone. The stress response to anemia is faster in the spleens of p53(-/-) mice, as shown by the higher levels of colony forming units erythroids and the increase in the CD34/c-kit double positive population. Our results show that p53 antagonizes GR-mediated ebl expansion and demonstrate for the first time that p53-GR cross-talk is important in a physiological process in vivo: stress erythropoiesis.

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