Hematopoietic, angiogenic and eye defects in Meis1 mutant animals.
Meis1 and Hoxa9 expression is upregulated by retroviral integration in murine myeloid leukemias and in human leukemias carrying MLL translocations. Both genes also cooperate to induce leukemia in a mouse leukemia acceleration assay, which can be explained, in part, by their physical interaction with each other as well as the PBX family of homeodomain proteins. Here we show that Meis1-deficient embryos have partially duplicated retinas and smaller lenses than normal. They also fail to produce megakaryocytes, display extensive hemorrhaging, and die by embryonic day 14.5. In addition, Meis1-deficient embryos lack well-formed capillaries, although larger blood vessels are normal. Definitive myeloerythroid lineages are present in the mutant embryos, but the total numbers of colony-forming cells are dramatically reduced. Mutant fetal liver cells also fail to radioprotect lethally irradiated animals and they compete poorly in repopulation assays even though they can repopulate all hematopoietic lineages. These and other studies showing that Meis1 is expressed at high levels in hematopoietic stem cells (HSCs) suggest that Meis1 may also be required for the proliferation/self-renewal of the HSC.
Hisa
Tomoyuki
T
Center for Cancer Research, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
Spence
Sally E
SE
Rachel
Rivka A
RA
Fujita
Masami
M
Nakamura
Takuro
T
Ward
Jerrold M
JM
Devor-Henneman
Deborah E
DE
Saiki
Yuriko
Y
Kutsuna
Haruo
H
Tessarollo
Lino
L
Jenkins
Nancy A
NA
Copeland
Neal G
NG
D000818:Animals; D017690:Cell Transplantation; D004622:Embryo, Mammalian / Q000098:blood supply / Q000166:cytology; D015672:Erythroid Precursor Cells / Q000166:cytology; D005124:Eye Abnormalities / Q000209:etiology*; D005260:Female; D005333:Fetus / Q000166:cytology; D018390:Gene Targeting; D018095:Germ-Line Mutation; D006410:Hematopoiesis; D006470:Hemorrhage / Q000209:etiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000196:embryology; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D023461:Myeloid Progenitor Cells / Q000166:cytology; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000209:etiology*
D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins