The Hox cofactors Meis1 and Pbx act upstream of gata1 to regulate primitive hematopoiesis

Abstract

During vertebrate development, the initial wave of hematopoiesis produces cells that help to shape the developing circulatory system and oxygenate the early embryo. The differentiation of primitive erythroid and myeloid cells occurs within a short transitory period, and is subject to precise molecular regulation by a hierarchical cascade of transcription factors. The TALE-class homeodomain transcription factors Meis and Pbx function to regulate embryonic hematopoiesis, but it is not known where Meis and Pbx proteins participate in the hematopoietic transcription factor cascade. To address these questions, we have ablated Meis1 and Pbx proteins in zebrafish, and characterized their molecular effects on known markers of primitive hematopoiesis. Embryos lacking Meis1 and Pbx exhibit a severe reduction in the expression of gata1, the earliest marker of erythroid cell fate, and fail to produce visible circulating blood cells. Concomitant with a loss of gata1, Meis1- and Pbx-depleted embryos exhibit downregulated embryonic hemoglobin (hbae3) expression, and possess increased numbers of pu.1-positive myeloid cells. gata1-overexpression rescues hbae3 expression in Pbx-depleted; meis1-morphant embryos, placing Pbx and Meis1 upstream of gata1 in the erythropoietic transcription factor hierarchy. Our study conclusively demonstrates that Meis1 and Pbx act to specify the erythropoietic cell lineage and inhibit myelopoiesis.

Hematopoietic Stem Cell Development: Using the Zebrafish to Identify the Signaling Networks and Physical Forces Regulating Hematopoiesis

“…The zinc finger transcription factor gata1 is expressed in the PLM and is considered the principal regulator of erythropoiesis, as evident in the gata1 mutant vlad tepes (vlt m651 ), which has few circulating red blood cells, but normal to enhanced production of myeloid cell types (Lyons et al, 2002). Recent knockdown studies have shown that pbx and meis1 act upstream of gata1 to affect primitive erythropoiesis (Pillay et al, 2010). spi1 is a central regulator of myeloid fate during the primitive wave (Hsu et al, 2004;Lieschke et al, 2002;Ward et al, 2003).…”

The role of meis1 in primitive and definitive hematopoiesis during zebrafish development

“…37 They proposed that meis1 acts upstream of gata1 and suggested that this was caused by a modest reduction in the level of the gata1 transcript. 37 We obtained several lines of evidence for a possible alternative model in which meis1 is required for terminal erythroid differentiation during primitive hematopoiesis in a gata1-independent manner. First, we observed in meis1 MO-injected Tg(gata1:EGFP) transgenic embryos that immature erythroid cells accumulated in the ICM for at least 48 hpf.…”

A GWAS sequence variant for platelet volume marks an alternative DNM3 promoter in megakaryocytes near a MEIS1 binding site

“…8,9 Third, gene knockout in mice results in early embryonic lethality with a complete lack of megakaryopoiesis, 10,11 and knockdown studies of meis1 in zebrafish showed major effects on both hematopoiesis and vasculogenesis, confirming the abrogation of the formation of thrombocytes, the fish equivalent of MKs and PLTs. 12,13 Finally, little is known about how MEIS1 regulates megakaryopoiesis, resulting in these striking phenotypes.…”