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Proc Natl Acad Sci U S A 2017 Jun 06;11423:5814-5821. doi: 10.1073/pnas.1610615114.
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Dissecting BMP signaling input into the gene regulatory networks driving specification of the blood stem cell lineage.

Kirmizitas A , Meiklejohn S , Ciau-Uitz A , Stephenson R , Patient R .

Hematopoietic stem cells (HSCs) that sustain lifelong blood production are created during embryogenesis. They emerge from a specialized endothelial population, termed hemogenic endothelium (HE), located in the ventral wall of the dorsal aorta (DA). In Xenopus, we have been studying the gene regulatory networks (GRNs) required for the formation of HSCs, and critically found that the hemogenic potential is defined at an earlier time point when precursors to the DA express hematopoietic as well as endothelial genes, in the definitive hemangioblasts (DHs). The GRN for DH programming has been constructed and, here, we show that bone morphogenetic protein (BMP) signaling is essential for the initiation of this GRN. BMP2, -4, and -7 are the principal ligands expressed in the lineage forming the HE. To investigate the requirement and timing of all BMP signaling in HSC ontogeny, we have used a transgenic line, which inducibly expresses an inhibitor of BMP signaling, Noggin, as well as a chemical inhibitor of BMP receptors, DMH1, and described the inputs from BMP signaling into the DH GRN and the HE, as well as into primitive hematopoiesis. BMP signaling is required in at least three points in DH programming: first to initiate the DH GRN through gata2 expression, then for kdr expression to enable the DH to respond to vascular endothelial growth factor A (VEGFA) ligand from the somites, and finally for gata2 expression in the DA, but is dispensable for HE specification after hemangioblasts have been formed.

PubMed ID: 28584091
PMC ID: PMC5468621
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: acvr1 acvr2a acvr2b acvrl1 alk aplnr bmp10 bmp2 bmp4 bmp5 bmp6 bmp7.1 bmp8 bmpr1a bmpr1b bmpr2 dll4 efnb2 etv2 fli1 gata2 gdf2 gfi1 grn hba3 hhex kdr lmo2 lmo3 mpo myc nog notch1 pecam1 runx1 smad1 smad2 spib tal1 tek tgfb1 vegfa
GO keywords: BMP signaling pathway [+]

Article Images: [+] show captions
References [+] :
Beck, Temporal requirement for bone morphogenetic proteins in regeneration of the tail and limb of Xenopus tadpoles. 2006, Pubmed, Xenbase