c-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo

2008
Article

Résumé

The c-myc proto-oncogene, which is crucial for the progression of many human cancers, has been implicated in key cellular processes in diverse cell types, including endothelial cells that line the blood vessels and are critical for angiogenesis. The de novo differentiation of endothelial cells is known as vasculogenesis, whereas the growth of new blood vessels from pre-existing vessels is known as angiogenesis. To ascertain the function of c-myc in vascular development, we deleted c-myc in selected cell lineages. Embryos lacking c-myc in endothelial and hematopoietic lineages phenocopied those lacking c-myc in the entire embryo proper. At embryonic day (E) 10.5, both mutant embryos were grossly normal, had initiated primitive hematopoiesis, and both survived until E11.5-12.5, longer than the complete null. However, they progressively developed defective hematopoiesis and angiogenesis. The majority of embryos lacking c-myc specifically in hematopoietic cells phenocopied those lacking c-myc in endothelial and hematopoietic lineages, with impaired definitive hematopoiesis as well as angiogenic remodeling. c-myc is required for embryonic hematopoietic stem cell differentiation, through a cell-autonomous mechanism. Surprisingly, c-myc is not required for vasculogenesis in the embryo. c-myc deletion in endothelial cells does not abrogate endothelial proliferation, survival, migration or capillary formation. Embryos lacking c-myc in a majority of endothelial cells can survive beyond E12.5. Our findings reveal that hematopoiesis is a major function of c-myc in embryos and support the notion that c-myc functions in selected cell lineages rather than in a ubiquitous manner in mammalian development.

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https://infoscience.epfl.ch/record/160892?ln=fr

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2008
Article

Résumé

Official source

https://infoscience.epfl.ch/record/160892?ln=fr

À propos de ce résultat

Concepts associés (20)

Concepts associés

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Publications associées (3)

Publications associées

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The nuclear protein c-Myc is one of the most potent proto-oncogenes described. Its expression is found to be deregulated in more than 50 percent of human cancers, where it has been shown to control a number of biological processes including driving proliferation, cell growth and angiogenesis while inhibiting differentiation. The effects of c-Myc are highly cell type specific and include cell autonomous and non-cell autonomous processes. In order to examine the effect of excess amounts of c-Myc in bone, we have generated a mouse line expressing the tTA transactivator under the control of the mouse 2.3 kb col1a1 promoter (named Col1a1::tTA), which directs transgene expression to mature osteoblasts. By combining this transgene with the Tet-O-Myc allele, we generated a Col1a1::tTA; Tet-O-Myc double transgenic mouse model in which it is possible to inducibly express human c-MYC in osteoblasts during development and in the adult. We document that the used 'tet-off' system directs transgene expression to bones and that c-MYC can be completely repressed by treatment with doxycycline. Using this mouse model, we demonstrate that overexpression of c-MYC leads to remarkable changes in mutant bones, which depend greatly in their severity on the developmental time point of c-MYC induction. Unrestricted c-MYC expression, starting with the first emergence of mature osteoblasts in the fetal skeleton (∼E14.0), leads to lethality of the mutants at birth; their bones are shortened and thicker than in controls. Later induction of c-MYC allows survival, but leads to significant changes in bone morphology. Mutant bones develop a very irregular bone structure with signs of excessive bone formation. Surprisingly, this also correlates with definite signs of excessive osteoclast activity, which explains the formation of cavities seen in the bone matrix. Osteoblasts not only produce bone matrix, they are also very important niche cells for hematopoietic cells, especially for hematopoietic stem cells and B cells. We find that c-MYC overexpression severely impairs B lymphopoiesis and also observe signs of extramedullary hematopoiesis in the spleen, which is indicative of a compromised HSC environment in the bone marrow. Most strikingly, these animals develop frank osteosarcomas leading to a much reduced life span. Tumors arise in various bones, with the ribs and hips being the most prominent sites. These c-MYC driven tumors are very aggressive as is evident by their capacity to spontaneously metastasize to lung and liver, a rather rare phenomenon in mouse models, indicating that these tumors share important aspects of human osteosarcomas. Molecular analysis of c-MYC overexpressing osteoblasts has revealed a defect in their terminal differentiation program, rendering them incapable to progress from a relatively immature proliferative to a quiescent, calcified matrix producing state. To our knowledge this is the first report of experimental osteosarcoma formation, originating from a mature and lineage committed osteoblast population indicating that c-MYC may be able to de-differentiate more mature cells. In summary, our novel conditional mouse model showed that c-MYC expression in mature osteoblasts can lead to the formation of highly aggressive and metastatic osteosarcomas, a lethal disease in humans. This model will be the basis for further studies elucidating the molecular effects of c-MYC on de-differentiation and metastasis formation, processes, which remain poorly understood but are critical events in highly malignant cancers.

EPFL2009

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The Notch signaling pathway regulates many aspects of embryonic development, as well as differentiation processes and tissue homeostasis in multiple adult organ systems. Disregulation of Notch signaling is associated with several human disorders, including cancer. In the last decade, it became evident that Notch signaling plays important roles within the hematopoietic and immune systems. Notch plays an essential role in the development of embryonic hematopoietic stem cells and influences multiple lineage decisions of developing lymphoid and myeloid cells. Moreover, recent evidence suggests that Notch is an important modulator of T cell-mediated immune responses. In this review, we discuss Notch signaling in hematopoiesis, lymphocyte development, and function as well as in T cell acute lymphoblastic leukemia.

2010

Chargement

Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function

Armin Ehninger

The c-Myc protein has been implicated in playing a pivotal role in regulating the expression of a large number of genes involved in many aspects of cellular function. Consistent with this view, embryos lacking the c-myc gene exhibit severe developmental defects and die before midgestation. Here, we show that Sox2Cre-mediated deletion of the conditional c-myc(flox) allele specifically in the epiblast (hence trophoectoderm and primitive endoderm structures are wild type) rescues the majority of developmental abnormalities previously characterized in c-myc knockout embryos, indicating that they are secondary defects and arise as a result of placental insufficiency. Epiblast-restricted c-Myc-null embryos appear morphologically normal and do not exhibit any obvious proliferation defects. Nonetheless, these embryos are severely anemic and die before E12. c-Myc-deficient embryos exhibit fetal liver hypoplasia, apoptosis of erythrocyte precursors and functionally defective definitive hematopoietic stem/progenitor cells. Specific deletion of c-myc(flox) in hemogenic or hepatocytic lineages validate the hematopoietic-specific requirement of c-Myc in the embryo proper and provide in vivo evidence to support a synergism between hematopoietic and liver development. Our results reveal for the first time that physiological levels of c-Myc are essential for cell survival and demonstrate that, in contrast to most other embryonic lineages, erythroblasts and hematopoietic stem/progenitor cells are particularly dependent on c-Myc function.

2008

Chargement

EPFL2009