LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis

Takahiro Maeda, Keisuke Ito, Taha Merghoub, Laura Poliseno, Robin M. Hobbs, Guocan Wang, Lin Dong, Manami Maeda, Louis C. Dore, Arthur Zelent, Lucio Luzzatto, Julie Teruya-Feldstein, Mitchell J. Weiss, Pier Paolo Pandolfi

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)527-540
Number of pages14
JournalDevelopmental Cell
Volume17
Issue number4
DOIs
StatePublished - Oct 20 2009
Externally publishedYes

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Erythropoiesis
Cell death
Transcription
Anemia
Cell Death
Embryonic Structures
Apoptosis
Erythroblasts
Transcription Factors
Up-Regulation
Phenotype

Keywords

  • DEVBIO

ASJC Scopus subject areas

  • Developmental Biology

Cite this

LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis. / Maeda, Takahiro; Ito, Keisuke; Merghoub, Taha; Poliseno, Laura; Hobbs, Robin M.; Wang, Guocan; Dong, Lin; Maeda, Manami; Dore, Louis C.; Zelent, Arthur; Luzzatto, Lucio; Teruya-Feldstein, Julie; Weiss, Mitchell J.; Pandolfi, Pier Paolo.

In: Developmental Cell, Vol. 17, No. 4, 20.10.2009, p. 527-540.

Research output: Contribution to journalArticle

Maeda, T, Ito, K, Merghoub, T, Poliseno, L, Hobbs, RM, Wang, G, Dong, L, Maeda, M, Dore, LC, Zelent, A, Luzzatto, L, Teruya-Feldstein, J, Weiss, MJ & Pandolfi, PP 2009, 'LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis', Developmental Cell, vol. 17, no. 4, pp. 527-540. https://doi.org/10.1016/j.devcel.2009.09.005
Maeda, Takahiro ; Ito, Keisuke ; Merghoub, Taha ; Poliseno, Laura ; Hobbs, Robin M. ; Wang, Guocan ; Dong, Lin ; Maeda, Manami ; Dore, Louis C. ; Zelent, Arthur ; Luzzatto, Lucio ; Teruya-Feldstein, Julie ; Weiss, Mitchell J. ; Pandolfi, Pier Paolo. / LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis. In: Developmental Cell. 2009 ; Vol. 17, No. 4. pp. 527-540.
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