Notch mediates Wnt and BMP signals in the early separation of smooth muscle progenitors and blood/endothelial common progenitors

Abstract

During embryonic development in amniotes, the extraembryonic mesoderm, where the earliest hematopoiesis and vasculogenesis take place, also generates smooth muscle cells (SMCs). It is not well understood how the differentiation of SMCs is linked to that of blood (BCs) and endothelial (ECs) cells. Here we show that, in the chick embryo, the SMC lineage is marked by the expression of a bHLH transcription factor, dHand. Notch activity in nascent ventral mesoderm cells promotes SMC progenitor formation and mediates the separation of SMC and BC/EC common progenitors marked by another bHLH factor, Scl. This is achieved by crosstalk with the BMP and Wnt pathways, which are involved in mesoderm ventralization and SMC lineage induction, respectively. Our findings reveal a novel role of the Notch pathway in early ventral mesoderm differentiation, and suggest a stepwise separation among its three main lineages, first between SMC progenitors and BC/EC common progenitors, and then between BCs and ECs.

Dynamic expression of Endoglin, a TGF-beta co-receptor, during pre-circulation vascular development in chick

“…1A, 2A; arrows). The extraembryonic mesoderm at this stage strongly expresses hemangioblast, hematopoietic and endothelial precursor markers such as Gata2, Scl, Lmo2, Ets1 and Vegfr2 Minko et al, 2003;Nakazawa et al, 2006;Shin et al, 2009), indicating that Endoglin expression does correlate with the initial steps of endothelial precursor specification.…”

“…Its expression pattern in the extraembryonic regions and in pre-circulation development has not been examined. We generated an anti-sense probe corresponding to amino acid residues 111-304 of the full length chick Endoglin (see Materials and Methods), and performed whole-mount in situ hybridization on embryos from stage HH4, when blood/endothelial progenitors start to be generated from the posterior primitive streak Nakazawa et al, 2006;Shin et al, 2009), to HH13, when circulation is initiated.…”

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

“…Activation of the NOTCH pathway in human mesenchymal or ESCs similarly induces SMC differentiation (Kurpinski et al, 2010). In the chick embryo, NOTCH activity in the ventral mesoderm mediates the balance between blood or endothelial and smooth muscle progenitors, and promotes the formation of the latter (Shin et al, 2009). In order to investigate whether NOTCH similarly regulates mesoderm cell fate acquisition in the gastrulating mouse embryo, we examined the formation of specific mesoderm types in N1ICD epi embryos.…”

Primitive and definitive erythropoiesis in the yolk sac: a birds eye view

“…2D). Yolk sac somatic mesoderm contains mainly smooth muscle cells that line the extraembryonic ectoderm (Adamstone, 1948;Oppenheim, 1966;Pierce, 1933;Shin et al, 2009;Wu et al, 2001) (Fig. 2D).…”

“…Small and infrequent blood islands with differentiated blood and endothelial cells have also been observed in the extraembryonic somatopleure in our analyses (unpublished data) (Alev et al, 2010), suggesting that blood and endothelial lineages do not segregate completely into the splanchnopleure during early extraembryonic mesoderm patterning. Among these three lineages, progenitors for the smooth muscle cells, contributing to both the somatopleure and splanchnopleure, separate first from the other two soon after their ingression through the primitive streak (Shin et al, 2009), followed by (Adelmann, 1966;Ruckert, 1906)]. This confusion, still outstanding today, is due to three main observations already apparent to embryologists a century ago (Ruckert, 1906): 1) prior to circulation, aggregates can be observed in the area vasculosa that are associated with both vasculogenesis and hematopoiesis; 2) aggregates can be observed both before and after the appearance of vascular endothelial cells; and 3) aggregates observed before the appearance of vascular endothelial cells are associated more with the territory of vasculogenesis than with that of hematopoiesis.…”