Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function.
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.
Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, School of Life Science, 1066 Epalinges, Switzerland.
Nicole C
NC
Dubois
Christelle
C
Adolphe
Armin
A
Ehninger
Rong A
RA
Wang
Elisabeth J
EJ
Robertson
Andreas
A
Trumpp
D000483:Alleles; D000818:Animals; D002470:Cell Survival; D004900:Erythroblasts / Q000166:cytology / Q000502:physiology*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009024:Morphogenesis; D010920:Placenta / Q000502:physiology*; D011247:Pregnancy; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
D016271:Proto-Oncogene Proteins c-myc