Marella de Bruijn

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.