Transcriptional profiling of adult haematopoietic stem cells (HSCs) and their differentiating daughters has given insights into lineage fate choice. So far, analysis of the expression program of haematopoetic stem cells arising during development has been lacking, partly because sufficient knowledge has only recently been gathered on the ontogeny of haematopoietic stem cells to allow their isolation from embryos.

Daley and colleagues (Cell Stem Cell 11, 710–714; 2012) have used surface markers to isolate emerging HSCs from the haematopoietic sites of developing embryos, including the yolk sac, placenta and ventral dorsal aorta, as well as from adult bone marrow and embryonic stem cells differentiating to embryoid bodies. The authors combined genome-wide expression profiling with gene regulatory network analysis to delineate three distinct global transcriptional states during haematopoietic development. They observed that HSCs emerging from the dorsal aorta initially exhibit a gene expression profile close to that of macrophages. They also uncovered that HSCs derived from embryoid bodies, despite displaying a transcription program most related to definitive HSCs from the bone marrow, seem deficient in Notch signalling, perhaps explaining their aberrant lymphopoiesis in functional tests. Finally, the authors use their data to identify known and novel transcriptional regulators of HSC ontogeny, which they functionally test using a loss-of-function approach in zebrafish. This resource will be useful to understand developmental haematopoiesis and to plan direct differentiation of pluripotent cells to HSCs for eventual therapeutic purposes.