The first adult-repopulating hematopoietic stem cells (HSCs) are detected starting at day 10.5 of gestation in the aorta-gonads-mesonephros (AGM) region of the mouse embryo. Despite its importance in initiating HSC production, very little is currently known about the regulators that control HSC emergence in the AGM. We have therefore further defined the location of HSCs in the AGM and incorporated this information into a spatial and temporal comparative gene expression analysis of the AGM. The comparisons included gene expression profiling (1) in the newly identified HSC-containing region as compared with the region devoid of HSCs, (2) before and after HSC emergence in the AGM microenvironment and (3) on populations enriched for HSCs and their putative precursors. Two genes found to be upregulated at the time and place where HSCs are first detected, the cyclin-dependent kinase inhibitor p57Kip2/Cdkn1c and the Insulin-like growth factor 2, were chosen for further analysis. We demonstrate here that they play a novel role in AGM hematopoiesis. Interestingly, many genes involved in the development of the tissues surrounding the dorsal aorta are also upregulated during HSC emergence, suggesting that the regulation of HSC generation occurs in coordination with the development of other organs.
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