Nonredundant roles for Runx1 alternative promoters reflect their activity at discrete stages of developmental hematopoiesis.
The transcription factor Runx1 is a pivotal regulator of definitive hematopoiesis in mouse ontogeny. Vertebrate Runx1 is transcribed from 2 promoters, the distal P1 and proximal P2, which provide a paradigm of the complex transcriptional and translational control of Runx1 function. However, very little is known about the biologic relevance of alternative Runx1 promoter usage in definitive hematopoietic cell emergence. Here we report that both promoters are active at the very onset of definitive hematopoiesis, with a skewing toward the P2. Moreover, functional and morphologic analysis of a novel P1-null and an attenuated P2 mouse model revealed that although both promoters play important nonredundant roles in the emergence of definitive hematopoietic cells, the proximal P2 was most critically required for this. The nature of the observed phenotypes is indicative of a differential contribution of the P1 and P2 promoters to the control of overall Runx1 levels, where and when this is most critically required. In addition, the dynamic expression of P1-Runx1 and P2-Runx1 points at a requirement for Runx1 early in development, when the P2 is still the prevalent promoter in the emerging hemogenic endothelium and/or first committed hematopoietic cells.
Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom.
Thomas
T
Bee
Gemma
G
Swiers
Sawako
S
Muroi
Amir
A
Pozner
Wade
W
Nottingham
Ana Cristina
AC
Santos
Pik-Shan
PS
Li
Ichiro
I
Taniuchi
Marella F T R
MF
de Bruijn
D000375:Aging / Q000235:genetics; D000483:Alleles; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002449:Cell Aggregation; D002452:Cell Count; D003114:Colony-Forming Units Assay; D050676:Core Binding Factor Alpha 2 Subunit / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D020964:Embryo Loss / Q000235:genetics / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D056426:Genetic Loci / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*
D015820:Cadherins; D050676:Core Binding Factor Alpha 2 Subunit; C493726:Runx1 protein, mouse; D049452:Green Fluorescent Proteins; D017493:Leukocyte Common Antigens