The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo.
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.
Azcoitia
Valeria
V
Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC UAM, Campus de Cantoblanco, Madrid, Spain.
Aracil
Miguel
M
Martínez-A
Carlos
C
Torres
Miguel
M
D000818:Animals; D001011:Aorta / Q000378:metabolism; D015139:Blotting, Southern; D015153:Blotting, Western; D019070:Cell Lineage; D002469:Cell Separation; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D005434:Flow Cytometry; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000196:embryology; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D008650:Mesonephros / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D018919:Neovascularization, Physiologic; D010641:Phenotype; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014469:Umbilical Arteries / Q000166:cytology
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D040201:Platelet Membrane Glycoprotein IIb; D011518:Proto-Oncogene Proteins; C493726:Runx1 protein, mouse; D014157:Transcription Factors