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LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis.

ABSTRACT: GATA-1-dependent transcription is essential for erythroid differentiation and maturation. Suppression of programmed cell death is also thought to be critical for this process; however, the link between these two features of erythropoiesis has remained elusive. Here, we show that the POZ-Krüppel family transcription factor, LRF (also known as Zbtb7a/Pokemon), is a direct target of GATA1 and plays an essential antiapoptotic role during terminal erythroid differentiation. We find that loss of Lrf leads to lethal anemia in embryos, due to increased apoptosis of late-stage erythroblasts. This programmed cell death is Arf and p53 independent and is instead mediated by upregulation of the proapoptotic factor Bim. We identify Lrf as a direct repressor of Bim transcription. In strong support of this mechanism, genetic Bim loss delays the lethality of Lrf-deficient embryos and rescues their anemia phenotype. Thus, our data define a key transcriptional cascade for effective erythropoiesis, whereby GATA-1 suppresses BIM-mediated apoptosis via LRF.

SUBMITTER: Maeda T 

PROVIDER: S-EPMC3134301 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis.

Maeda Takahiro T   Ito Keisuke K   Merghoub Taha T   Poliseno Laura L   Hobbs Robin M RM   Wang Guocan G   Dong Lin L   Maeda Manami M   Dore Louis C LC   Zelent Arthur A   Luzzatto Lucio L   Teruya-Feldstein Julie J   Weiss Mitchell J MJ   Pandolfi Pier Paolo PP  

Developmental cell 20091001 4

GATA-1-dependent transcription is essential for erythroid differentiation and maturation. Suppression of programmed cell death is also thought to be critical for this process; however, the link between these two features of erythropoiesis has remained elusive. Here, we show that the POZ-Krüppel family transcription factor, LRF (also known as Zbtb7a/Pokemon), is a direct target of GATA1 and plays an essential antiapoptotic role during terminal erythroid differentiation. We find that loss of Lrf l  ...[more]