Selected publications

• de Bruijn M F, Speck N A, Peeters M C, and Dzierzak E (2000) Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. EMBO J, 19(11):2465-74.

• de Bruijn Marella FTR, Ma Xiaoqian, Robin Catherine, Ottersbach Katrin, Sanchez Maria-Jose, and Dzierzak Elaine (2002) Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta. Immunity, 16(5):673-83.

• North Trista E, de Bruijn Marella FTR, Stacy Terryl, Talebian Laleh, Lind Evan, Robin Catherine, Binder Michael, Dzierzak Elaine, and Speck Nancy A (2002) Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity, 16(5):661-72.

• Nottingham Wade T, Jarratt Andrew, Burgess Matthew, Speck Caroline L, Cheng Jan-Fang, Prabhakar Shyam, Rubin Eddy M, Li Pik-Shan, Sloane-Stanley Jackie, Kong-A-San John, and de Bruijn Marella FTR (2007) Runx1-mediated hematopoietic stem-cell emergence is controlled by a Gata/Ets/SCL-regulated enhancer. Blood, 110(13):4188-97.

• Knezevic Kathy, Bee Thomas, Wilson Nicola K, Janes Mary E, Kinston Sarah, Polderdijk Stephanie, Kolb-Kokocinski Anja, Ottersbach Katrin, Pencovich Niv, Groner Yoram, de Bruijn Marella, Gottgens Berthold, and Pimanda John E (2011) A Runx1-Smad6 rheostat controls Runx1 activity during embryonic hematopoiesis. Mol Cell Biol, 31(14):2817-26.

A central question in the stem cell field is what are the cellular and molecular mechanisms that underlie the generation and maintenance of the different types of stem cells.  The focus of our research is the origin of the haemopoietic stem cells (HSCs) during mouse embryonic development. The first HSCs appear in the aorta-gonad-mesonephros (AGM) region and in the vitelline and umbilical arteries of the midgestation mouse embryo. Runx1, the gene encoding the DNA- binding subunit of the heterodimeric transcription factor Runx1:CBFb, is expressed at these sites prior to the generation of functional HSCs, and is absolutely required for HSCs generation. The specific temporal and spatial pattern of Runx1 expression suggests a critical role for Runx1 in the specification of precursor cells towards the haemopoietic lineage and in the establishment and maintenance of haemopoietic differentiation programs. It also suggests that factors regulating the expression of Runx1 are important to the development of the haemopoietic system.
The questions our research addresses are:

1. What regulatory mechanisms control Runx1 expression in the haemogenic sites?
2. What are the Runx1-regulated target genes in the first emerging HSCs?
   

Answers to these questions will increase our understanding of the intrinsic signals required for HSC specification and maintenance. Comparison of target genes and regulatory mechanisms between different stem cell populations in the embryo may reveal common and diverging molecular themes in early stem cell specification and development. Such insights could be important to the development of new and efficient therapeutic strategies. Additionally, RUNX1 mutations are involved in human leukaemia, and identification of Runx1 target genes could help to elucidate the molecular mechanisms of leukaemia onset and progression.

Definitive HSCs are first found in cell clusters that bud from the floor of the dorsal aorta.

A -  Schematic representation of this process.

B -  The Runx1 +23 enhancer identified in our laboratory specifically targets haemopoietic stem and progenitor cells in the aortic clusters.