Differential Etv2 threshold requirement for endothelial and erythropoietic development

Endothelial and erythropoietic lineages arise from a common developmental progenitor. Etv2 is a master transcriptional regulator required for the development of both lineages. However, the mechanisms through which Etv2 initiates the gene-regulatory networks (GRNs) for endothelial and erythropoietic...

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Bibliographic Details
Published inCell reports (Cambridge) Vol. 39; no. 9; p. 110881
Main Authors Sinha, Tanvi, Lammerts van Bueren, Kelly, Dickel, Diane E., Zlatanova, Ivana, Thomas, Reuben, Lizama, Carlos O., Xu, Shan-Mei, Zovein, Ann C., Ikegami, Kohta, Moskowitz, Ivan P., Pollard, Katherine S., Pennacchio, Len A., Black, Brian L.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 31.05.2022
Elsevier
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Summary:Endothelial and erythropoietic lineages arise from a common developmental progenitor. Etv2 is a master transcriptional regulator required for the development of both lineages. However, the mechanisms through which Etv2 initiates the gene-regulatory networks (GRNs) for endothelial and erythropoietic specification and how the two GRNs diverge downstream of Etv2 remain incompletely understood. Here, by analyzing a hypomorphic Etv2 mutant, we demonstrate different threshold requirements for initiation of the downstream GRNs for endothelial and erythropoietic development. We show that Etv2 functions directly in a coherent feedforward transcriptional network for vascular endothelial development, and a low level of Etv2 expression is sufficient to induce and sustain the endothelial GRN. In contrast, Etv2 induces the erythropoietic GRN indirectly via activation of Tal1, which requires a significantly higher threshold of Etv2 to initiate and sustain erythropoietic development. These results provide important mechanistic insight into the divergence of the endothelial and erythropoietic lineages. [Display omitted] •Etv2 hypomorphic mutant mouse embryos have profound anemia and normal vasculature•Higher Etv2 expression is required for erythropoiesis than for vasculogenesis•Etv2 directly regulates the embryonic endothelial gene-regulatory network (GRN)•Etv2 indirectly regulates the embryonic erythropoietic GRN via Tal1 Sinha et al. demonstrate that the master regulatory transcription factor Etv2 directly regulates the mouse embryonic endothelial gene-regulatory network (GRN). In contrast, Etv2 regulates the erythropoietic GRN indirectly via the bHLH transcription factor Tal1, making erythropoiesis more sensitive than vasculogenesis to reduced Etv2 gene dosage.
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USDOE
AC02-05CH11231
AUTHOR CONTRIBUTIONS
Conceptualization, T.S., K.L.v.B., C.L., A.C.Z., K.I., I.P.M., and B.L.B.; methodology, T.S., D.E.D., L.A.P., and S.X.; formal analysis, T.S., K.L.v.B., R.T., and K.S.P.; investigation, T.S., K.L.v.B., I.Z., and D.E.D.; data curation, T.S. and R.T.; writing – original draft, T.S. and B.L.B.; writing – reviewing and editing, all authors; visualization, T.S. and B.L.B.; supervision, B.L.B.; project administration, B.L.B.; funding acquisition, B.L.B. All authors approved the final manuscript.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2022.110881