14-P018 The aorta–gonad–mesonephros microenvironment enhances haematopoietic differentiation of mouse embryonic stem cells: Assessing the role of the Notch signaling pathway

Haematopoiesis is one of the most extensively studied models to comprehend cellular differentiation and lineage commitment. It is now well established that blood cells emerge early during vertebrate ontogeny from mesodermal progenitors which also have the potential to generate endothelial and smooth muscle cells. However, the molecular and cellular mechanisms involved in the commitment of mesoderm towards the haematopoietic fate remain elusive. Gene expression studies, covering discrete transition stages of mesoderm differentiation, have reported the up-regulation of the transcription factor Sox7 at the onset of haematopoiesis. When cultured in haematopoietic permissive conditions, mesoderm precursors progressively lose Sox7 expression as they give rise to fully committed haematopoietic cells. To gain further insight into the role of Sox7 during this differentiation process, we made use of an inducible Sox7 mouse Embryonic Stem (ES) cell line, allowing us to switch Sox7 on and off at will. Upon enforced expression of Sox7, ES-derived blood precursors fail to differentiate and retain a highly proliferative potential. Moreover, differential gene expression analysis revealed that this transcription factor can maintain or reactivate a molecular program reminiscent of an early mesodermal progenitor. Altogether, our data suggest that Sox7 is involved in the expansion and maintenance of the earliest blood precursors. In the present study, we have explored the transcriptional activation of genes in the context of Sox7 sustained expression to identify its key transcriptional targets and integrate this Sox7-driven regulatory circuitry in the complex network of genes that regulates embryonic haematopoiesis.