Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice

HC Masuoka, TM Townes - Blood, The Journal of the American …, 2002 - ashpublications.org
HC Masuoka, TM Townes
Blood, The Journal of the American Society of Hematology, 2002ashpublications.org
Activating transcription factor (ATF) 4 is a ubiquitous basic leucine-zipper transcription factor
that is a member of the ATF/cyclic adenosine monophosphate responsive element–binding
(CREB) protein family. To determine the in vivo function of ATF4, the ATF4 gene in murine
embryonic stem cells was deleted and homozygous mutant mice were generated. ATF4 null
fetuses were severely anemic because of an impairment in fetal-liver definitive
hematopoiesis; the hematocrit in 15.5-day mutant fetuses was 0.15, whereas that in controls …
Abstract
Activating transcription factor (ATF) 4 is a ubiquitous basic leucine-zipper transcription factor that is a member of the ATF/cyclic adenosine monophosphate responsive element–binding (CREB) protein family. To determine the in vivo function of ATF4, the ATF4 gene in murine embryonic stem cells was deleted and homozygous mutant mice were generated. ATF4 null fetuses were severely anemic because of an impairment in fetal-liver definitive hematopoiesis; the hematocrit in 15.5-day mutant fetuses was 0.15, whereas that in controls was 0.35. The fetal livers in homozygous ATF4 mutants were pale and hypoplastic. In vitro culture of fetal-liver cells showed fewer hematopoietic progenitors per embryo and a dramatic decrease in the size of progenitor colonies. Culture of primary murine embryonic fibroblasts showed a proliferative defect. These results suggest that ATF4 is critical, in a cell-autonomous manner, for normal cellular proliferation, especially for the high-level proliferation required during fetal-liver hematopoiesis.
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