Differential Etv2 threshold requirement for endothelial and erythropoietic development

• Published in: Cell 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
• Language: English
• Published: United States Elsevier Inc 31.05.2022; Elsevier
• Subjects: Cell Biology; endothelial development; Endothelium - metabolism; erythropoiesis; Etv2; gene regulatory network; Gene Regulatory Networks; GRN; hematopoiesis; Tal1; Transcription Factors - metabolism; transcriptional regulation; yolk sac; hematopoiesis; GRN; Tal1; endothelial development; transcriptional regulation; CP: Molecular biology; Etv2; yolk sac; erythropoiesis; CP: Developmental biology; gene regulatory network
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110881

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.