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

Abstract

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.

The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization

“…This is most likely because of the timing and/or lower efficiency of the Cre recombination associated with this Cre line, as has been reported previously. 29 These in vivo data suggest that Zeb2 is not directly involved in the formation of hematopoietic clusters in the AGM but instead controls HSC/HPC differentiation potential and Lin Ϫ cKit ϩ progenitor mobilization (Figure 7 is a hypothetical model).…”

“…by guest www.bloodjournal.org From crossed with a Vav-iCre line 28 that produces the Cre recombinase specifically in hematopoietic cells (supplemental Figure 2A-B), but only after HSC formation. 29 Furthermore, the comparison of the phenotypes associated with Tie2-Cre-and Vav-iCre-mediated loss of Zeb2 allowed us to investigate at what stage in development the expression of Zeb2 is essential for hematopoiesis: before or after HSC formation. 16 In the Zeb2 Ϫ/⌬Vav-iCre embryos, a phenotype very similar to that seen in the Zeb2 Ϫ/⌬Tie2-Cre knockouts could be observed.…”

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

“…Nevertheless, we provide strong genetic evidence that c-Myc is not directly required for the formation of the embryonic vascular system. As described in the accompanying paper by He et al (He et al, 2008) abnormalities are present upon c-Myc deletion; however, they arise secondarily owing to the lack of hematopoietic cells (He et al, 2008).…”

c-Myc Signalling in the Genetic Mechanism of Polycystic Kidney Disease

“…Embryos with a hypomorphic N-Myc allele resulted in hypoplastic kidneys at e13.5 with normal developing structures, due to reduced cell proliferation in mesenchymal cells and ureteric bud (54). Germline c-Myc inactivation leads to small and developmentally-retarded embryos that die at e9.5-e10.5 (55), and similarly epiblast-restricted c-Myc conditional inactivation resulted in fetal demise at e11.5 (56,57) which precluded further analysis of c-Myc function in renal development as well as in adult renal homeostasis.…”