Dissecting BMP signaling input into the gene regulatory networks driving specification of the blood stem cell lineage.

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 , 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).

Transforming Growth Factor β Drives Hemogenic Endothelium Programming and the Transition to Hematopoietic Stem Cells.

Hematopoietic stem cells (HSCs) are self-renewing multipotent stem cells that generate mature blood lineages throughout life. They, together with hematopoietic progenitor cells (collectively known as HSPCs), emerge from hemogenic endothelium in the floor of the embryonic dorsal aorta by an endothelial-to-hematopoietic transition (EHT). Here we demonstrate that transforming growth factor β (TGFβ) is required for HSPC specification and that it regulates the expression of the Notch ligand Jagged1a in endothelial cells prior to EHT, in a striking parallel with the epithelial-to-mesenchymal transition (EMT).

Gtpbp2 is a positive regulator of Wnt signaling and maintains low levels of the Wnt negative regulator Axin.

Background: Canonical Wnt signals, transduced by stabilized β-catenin, play similar roles across animals in maintaining stem cell pluripotency, regulating cell differentiation, and instructing normal embryonic development. Dysregulated Wnt/β-catenin signaling causes diseases and birth defects, and a variety of regulatory processes control this pathway to ensure its proper function and integration with other signaling systems. We previously identified GTP-binding protein 2 (Gtpbp2) as a novel regulator of BMP signaling, however further exploration revealed that Gtpbp2 can also affect Wnt signaling, which is a novel finding reported here.

Developmental hematopoiesis: ontogeny, genetic programming and conservation.

Hematopoietic stem cells (HSCs) sustain blood production throughout life and are of pivotal importance in regenerative medicine. Although HSC generation from pluripotent stem cells would resolve their shortage for clinical applications, this has not yet been achieved mainly because of the poor mechanistic understanding of their programming. Bone marrow HSCs are first created during embryogenesis in the dorsal aorta (DA) of the midgestation conceptus, from where they migrate to the fetal liver and, eventually, the bone marrow.

Gtpbp2 is required for BMP signaling and mesoderm patterning in Xenopus embryos.

Smad proteins convey canonical intracellular signals for activated receptors in the TGFβ superfamily, but the activity of Smads and their impact on target genes are further regulated by a wide variety of cofactors and partner proteins. We have identified a new Smad1 partner, a GTPase named Gtpbp2 that is a distant relative of the translation factor eEf1a. Gtpbp2 affects canonical signaling in the BMP branch of the TGFβ superfamily, as morpholino knockdown of Gtpbp2 decreases, and overexpression of Gtpbp2 enhances, animal cap responses to BMP4.

VEGFA-dependent and -independent pathways synergise to drive Scl expression and initiate programming of the blood stem cell lineage in Xenopus.

The first haematopoietic stem cells share a common origin with the dorsal aorta and derive from putative adult haemangioblasts in the dorsal lateral plate (DLP) mesoderm. Here we show that the transcription factor (TF) stem cell leukaemia (Scl/Tal1) is crucial for development of these adult haemangioblasts in Xenopus and establish the regulatory cascade controlling its expression. We show that VEGFA produced in the somites is required to initiate adult haemangioblast programming in the adjacent DLP by establishing endogenous VEGFA signalling.

Mustn1 is essential for craniofacial chondrogenesis during Xenopus development.

Mustn1 is a vertebrate-specific protein that, in vitro, was showed to be essential for prechondrocyte function and thus it has the potential to regulate chondrogenesis during embryonic development. We use Xenopus laevis as a model to examine Mustn1 involvement in chondrogenesis. Previous work suggests that Mustn1 is necessary but not sufficient for chondrogenic proliferation and differentiation, as well as myogenic differentiation in vitro.