Newly formed mature hematopoietic cells are generated through a complex maturation process based on the differentiation of Hematopoietic Stem Cells (HSC). In the mouse embryo, HSCs are first detected in the Aorta-Gonade-Mesonephros (AGM) region at midgestation.
They arise from the major arteries and are thought to differentiate from a population of hemogenic endothelial cells (EC). Cellular events that occur during AGM-associated hematopoiesis are well-documented, but the underlying molecular mechanisms are still under investigation. The overall objective of the present project is to further our understanding of molecular regulations governing early production of HSCs from hemogenic ECs.
It is focused on the RUNX1 transcription factor, a key regulator of HSC production and a frequent target in human haematological malignancies. In mouse embryo, disruption of either Runx1 or its co-factor Cbfb leads to complete failure in HSC development. RUNX1 is known to govern this process at the level of hemogenic ECs and to mark all HSCs at midgestation.
However, since the requirement of CBFb in this process is poorly understood and the accurate function of RUNX1 is not known, the specific aims of this project are:
1) To describe the expression of the RUNX1 binding partner, CBFb, in midgestation aortic HSCs and ECs
2) To conditionally knockout Runx1 during different stages of the EC to HSC transition in the midgestation aorta.
For this purpose, transgenic mouse models will be generated and AGM-associated hematopoiesis will be analysed using a large panel of descriptive and functional approaches. Innovative methodologies will be undertaken to analyse the complex biological activity of RUNX1.
We will use fluorescent markers to follow genes expression and cell fate and also design a Cre-loxP recombination systems to conditionally disrupt Runx1 function. This study will allow us to explore in detail biological activity and function of both RUNX1 and CBFb in HSCs production.
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