The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo

Abstract

Homeodomain proteins of the Meis subfamily are expressed dynamically in several organs during embryogenesis and exert potent regulatory activity through their interaction with Hox proteins and other transcription factors. Here we show that Meis1 is expressed in the hematopoietic stem cell (HSC) compartment in the fetal liver, and in the primary sites of definitive hematopoiesis, including the aorta-gonad-mesonephros (AGM) mesenchyme, the hemogenic embryonic arterial endothelium, and hematopoietic clusters within the aorta, vitelline, and umbilical arteries. We inactivated the Meis1 gene in mice and found that Meis1 mutant mice die between embryonic days 11.5 and 14.5, showing internal hemorrhage, liver hypoplasia, and anemia. In Meis1 mutant mouse fetal liver and AGM, HSC compartments are severely underdeveloped and colony-forming potential is profoundly impaired. AGM mesenchymal cells expressing Runx1, an essential factor for definitive HSC specification, are almost absent in mutant mice. In addition, hematopoietic clusters in the dorsal aorta, vitelline, and umbilical arteries are reduced in size and number. These results show a requirement for Meis1 in the establishment of definitive hematopoiesis in the mouse embryo. Meis1 mutant mice also displayed complete agenesis of the megakaryocyte lineage and localized defects in vascular patterning, which may cause the hemorrhagic phenotype.

Platelets Play an Essential Role in Separating the Blood and Lymphatic Vasculatures During Embryonic Angiogenesis

“…8 The distribution of ectopic blood foci matches the pattern of nascent lymphatic vessels at E12.5 and E13.5 (Figure 1a through 1d), 1 and analysis of endothelial and lymphendothelial markers identified the ectopic blood foci as the recently formed lymphatic sacs, which were filled with erythrocytes ( Figure 1e through 1g and 1i through 1k). Meis1 is not expressed in blood vascular endothelial cells 8 or lymphatic endothelium (Figure 1h and 1i), suggesting a nonautonomous involvement of nonvascular cells.…”

“…Meis1 (myeloid ecotropic viral integration site 1) encodes a homeodomain transcription factor important for definitive hematopoietic stem cell development in the embryo and essential for megakaryocyte lineage development. 8 Here, through characterization of Meis1-deficient mice and targeted ablation of megakaryocytes/platelets, we demonstrate an essential role for platelets in the separation of the blood and lymphatic vasculature.…”

CD34+ hematopoietic stem-progenitor cell microRNA expression and function: A circuit diagram of differentiation control

“…miRNA-221 and -222 also may be more generalized inhibitors of hematopoietic differentiation, because our data (Table 2) predict that they also may regulate myeloid differentiation-associated molecules ( Fig. 2; MEIS1 and ETS1, both proteins shown to be involved in myeloid development (25,26), and FOS, which has been implicated in lymphopoiesis; ref. 27 and unpublished data).…”

Rethinking the proximodistal axis of the vertebrate limb in the molecular era

“…The Meis genes are more than just markers for the stylopod, as they may themselves play a role in proximal specification; since ectopic expression of these genes can reprogram proximodistal fate at least to some extent (Capdevila et al 1999;Meracader 2000). However, it is important to note that gene inactivation studies have indicated that neither of these genes is essential, at least individually, for normal limb development (Azcoitia et al 2005).…”