Fig. 5.

Summary of signaling events and downstream transcription factors driving specification of the blood stem cell lineage. The hemangioblast GRN commences with the expression of fli1, which is genetically upstream of gata2 and flk1/kdr (9). Meanwhile, TGFB signaling has an inhibitory effect on fli1 expression (44). BMP signaling, presumably through activation Smad transcription factors, together with Fli1, is first required for gata2 expression before stage 20 (*1) and then for kdr expression at stage 20 (*2) (current study). The genes that are affected consequentially at those stages are colored gray. VEGFA small isoform (VEGFA₁₂₂) then activates Kdr receptor which lead to the expression of scl/tal1 and hhex (14). Finally, BMP signaling is still required at stage 23–26 for the initiation of gata2 expression later in the DA (*3) (current study). Later, VEGFA medium isoform (VEGFA₁₇₀) from somites induces Notch1, which in turn is required for the maintenance of gata2 expression and induction of runx1 (14). The requirements for each signaling pathway are indicated by color-matching the text with the transcription factors. The three inputs from BMP signaling are shown with asterisks (*).