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Gfi1aa and Gfi1b set the pace for primitive erythroblast differentiation from hemangioblasts in the zebrafish embryo

Moore, Chris; Richens, Joanna L.; Hough, Yasmin; Ucanok, Deniz; Malla, Sunir; Sang, Fei; Chen, Yan; Elworthy, Stone; Wilkinson, Robert N.; Gering, Martin

Authors

Chris Moore

Joanna L. Richens

Yasmin Hough

Deniz Ucanok

Sunir Malla

FEI SANG Fei.Sang@nottingham.ac.uk
Research Fellow

Yan Chen

Stone Elworthy



Abstract

The transcriptional repressors Gfi1(a) and Gfi1b are epigenetic regulators with unique and overlapping roles in hematopoiesis. In different contexts, Gfi1 and Gfi1b restrict or promote cell proliferation, prevent apoptosis, influence cell fate decisions, and are essential for terminal differentiation. Here, we show in primitive red blood cells (prRBCs) that they can also set the pace for cellular differentiation. In zebrafish, prRBCs express 2 of 3 zebrafish Gfi1/ 1b paralogs, Gfi1aa and Gfi1b. The recently identified zebrafish gfi1aa gene trap allele qmc551 drives erythroid green fluorescent protein (GFP) instead of Gfi1aa expression, yet homozygous carriers have normal prRBCs. prRBCs display a maturation defect only after splice morpholino-mediated knockdown of Gfi1b in gfi1aaqmc551 homozygous embryos. To study the transcriptome of the Gfi1aa/1b double-depleted cells, we performed an RNA-Seq experi- ment on GFP-positive prRBCs sorted from 20-hour-old embryos that were heterozygous or homozygous for gfi1aaqmc551, as well as wt or morphant for gfi1b. We subsequently confirmed and extended these data in whole-mount in situ hybridization experiments on newly generated single- and double-mutant embryos. Combined, the data showed that in the absence of Gfi1aa, the synchronously developing prRBCs were delayed in activating late erythroid differentiation, as they struggled to suppress early erythroid and endothelial transcription programs. The latter highlighted the bipotent nature of the progenitors from which prRBCs arise. In the absence
of Gfi1aa, Gfi1b promoted erythroid differentiation as stepwise loss of wt gfi1b copies progressively delayed Gfi1aa-depleted prRBCs even further, showing that Gfi1aa and Gfi1b together set the pace for prRBC differentiation from hemangioblasts.

Journal Article Type Article
Publication Date Oct 23, 2018
Journal Blood Advances
Electronic ISSN 2473-9537
Publisher American Society of Hematology
Peer Reviewed Peer Reviewed
Volume 2
Issue 20
Pages 2589-2606
APA6 Citation Moore, C., Richens, J. L., Hough, Y., Ucanok, D., Malla, S., Sang, F., …Gering, M. (2018). Gfi1aa and Gfi1b set the pace for primitive erythroblast differentiation from hemangioblasts in the zebrafish embryo. Blood Advances, 2(20), 2589-2606. doi:10.1182/bloodadvances.2018020156
DOI https://doi.org/10.1182/bloodadvances.2018020156
Publisher URL http://www.bloodadvances.org/content/2/20/2589?sso-checked=true
Additional Information No embargo.

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