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First published online 11 June 2008
doi: 10.1242/dev.022707

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

Nicole C. Dubois^1,*, Christelle Adolphe¹, Armin Ehninger¹, Rong A. Wang², Elisabeth J. Robertson³ and Andreas Trumpp^1,

¹ Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC-Swiss Institute for Experimental Cancer Research, School of Life Science, 1066 Epalinges, Switzerland.
² Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, University of California, San Francisco, CA 94143, USA.
³ Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

Author for correspondence (e-mail: andreas.trumpp{at}epfl.ch)

Accepted 29 April 2008

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.

Key words: c-Myc, Hematopoietic stem cell, Placenta, Embryonic hematopoiesis, Fetal liver, Survival, Mouse

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